Melampomagnolide B derivatives

ABSTRACT

The present disclosure provides derivatives of melampomagnolide B (MMB), including carbonates, carbamates, and thiocarbamates. The derivatives may be synthesized via an MMB triazole intermediate. These derivatives are useful for treating cancer in humans.

CROSS REFERENCE TO RELATED APPLICATIONS

This application claims the priority of U.S. provisional application No.61/901,714, filed Nov. 8, 2013, which is hereby incorporated byreference in its entirety.

GOVERNMENTAL RIGHTS

This invention was made with government support under Grant No. CA158275awarded by the National Institutes of Health (NIH). The government hascertain rights to the invention.

FIELD OF THE INVENTION

This disclosure generally relates to a series of melampomagnolide B(MMB) derivatives, including carbamate, thiocarbamate and carbonatederivatives of MMB. These compounds exhibit potent anticancer activity.

BACKGROUND OF THE INVENTION

Parthenolide (PTL), an abundant sesquiterpene lactone found in themedicinal herb feverfew (Tanacetum parthenium), has undergone intensepharmacological research, especially for its antileukemic properties.Initial biomechanistic studies of PTL and its derivatives indicate thatthe compound promotes apoptosis by inhibiting the NF-kB transcriptionfactor complex, thereby downregulating antiapoptotic genes under NF-kBcontrol. PTL and its derivatives may also interfere with glutathionefunction, specifically glutathione's ability to sequester reactiveoxygen species. In culture, PTL induces robust apoptosis of primaryacute myeloid leukemia (AML) cells in culture. To overcome poorwater-solubility, PTL may be derivatized with an alkylamino, which canconvert into water-soluble salts. A series of fluorinated aminoderivatives of PTL exhibit activity in antiproliferative assays in HL-60(human promyelocytic leukemia) cells. PTL has also been the source ofseveral antileukemic compounds arising from chemical modification of thePTL molecule.

Melampomagnolide B (MMB), a melampolide originally isolated fromMagnolia grandiflora, is an antileukemic sesquiterpene with propertiessimilar to those of PTL. MMB has been synthesized via selenium oxideoxidation of the C10 methyl group of PTL, resulting in a concomitantconversion of the geometry of the C9-C10 double bond from trans to thecis geometry. MMB contains a primary OH group, providing a point ofattachment for derivatives with increased water solubility,bioavailability, and tissue targeting. Phase 1 clinical data fromdimethylaminoparthenolide (DMAPT), a synthetic aminoparthenolidederivative, indicated improved bioavailability and longer in vivohalf-lifes for PTL and MMB derivatives with increased water solubility.

SUMMARY OF THE INVENTION

Briefly, therefore, one aspect of the present disclosure encompassescompounds comprising Formula (I) or (II):

wherein:

-   -   X is O or S;    -   R¹ and R² are independently selected from the group consisting        of —NR³R⁴, —OR³, —O-alkyl-NR³R⁴, —SR³, —S-alkyl-NR³R⁴,        alkyl-C(O)NR³R⁴, and -alkyl-R⁵;    -   R³ is selected from the group consisting of hydrocarbyl,        substituted hydrocarbyl, and R⁵;    -   R⁴ is selected from the group consisting of hydrogen,        hydrocarbyl, and substituted hydrocarbyl;    -   R⁵ is an optionally substituted nitrogen-containing heterocyclic        ring;    -   one or more of R³ and R⁴ may form part of a ring or ring system        chosen from the group consisting of heterocyclic, substituted        heterocyclic, and combinations thereof; and    -   when R⁴ is hydrogen, R³ is selected from the group consisting of        alkyl, R⁵, and substituted hydrocarbyl having at least one        hydroxyl or R⁵.

Another aspect of the disclosure provides a process for preparing acompound comprising Formula (I) or (II). The process comprises (a)contacting a compound comprising Formula (III) with a triazole reagentto form a compound comprising Formula (IV). The process continues with(b) contacting the compound of Formula (IV) with a compound comprisingformula R¹—H to form a compound comprising Formula (I). The process isaccording to the following reaction scheme:

wherein:

-   -   X is O or S;    -   R¹ is selected from the group consisting of —NR³R⁴, —OR³,        —O-alkyl-NR³R⁴, —SR³, —S-alkyl-NR³R⁴, alkyl-C(O)NR³R⁴,        -alkyl-C(O)R⁵, and -alkyl-R⁵;    -   R³ is selected from the group consisting of hydrocarbyl,        substituted hydrocarbyl, and R⁵;    -   R⁴, R⁶, and R⁷ are independently selected from the group        consisting of hydrogen, hydrocarbyl, and substituted        hydrocarbyl;    -   R⁵ is an optionally substituted nitrogen-containing heterocyclic        ring;    -   one or more of R³ and R⁴ may form part of a ring or ring system        chosen from the group consisting of heterocyclic, substituted        heterocyclic, and combinations thereof; and    -   when R⁴ is hydrogen, R³ is selected from the group consisting of        alkyl, R⁵, and substituted hydrocarbyl having at least one        hydroxyl or R⁵.

Yet another aspect of the disclosure provides a method for inhibitinggrowth of a cancer cell. The method comprises contacting the cancer cellwith an amount of a compound comprising Formula (I) or (II), or a saltthereof, effective to inhibit growth of the cancer cell.

Other features and iterations of the invention are described in moredetail below.

BRIEF DESCRIPTION OF THE FIGURES

The application file contains at least one drawing executed in color.Copies of this patent application publication with color drawing(s) willbe provided by the Office upon request and payment of the necessary fee.

FIG. 1 shows the antileukemic activity of PTL, MMB, JMV 64, JMV 66, JMV69, and JMV 74 against the AML 052308 cell line as a function ofconcentration (μM) and percentage of cell viability.

FIG. 2 shows the antileukemic activity of PTL, MMB, JMV 57, JMV 58, JMV59, and JMV 61 against the AML 052308 cell line as a function ofconcentration (μM) and percentage of cell viability.

FIG. 3 shows the 24-hour M9's percentage of live cells relative tountreated cells for PTL, MMB, JMV 2-5, JMV 2-16, JMV 2-40, JMV 2-49, JVM2-35, JVM 2-41, and JVM 95 as a function of concentration (μM).

FIG. 4 shows the 24-hour M9's percentage of live cells relative tountreated cells for PTL, MMB, JMV 2-26, JMV 2-31, JMV 2-4, JMV 86, JVM90, and JVM 96 as a function of concentration (μM).

FIG. 5 shows the antileukemic activity of PTL, MMB, and JMV 88 againstthe M9 ENL cell line as a function of concentration (μM) and percentageof cell viability at 24 hours.

FIG. 6 shows the antileukemic activity of PTL, MMB, and JMV 88 againstthe AML 123009 cell line as a function of concentration (μM) andpercentage of cell viability.

FIG. 7 shows the antileukemic activity of PTL, MMB, and JMV 88 againstthe AML 100510 cell line as a function of concentration (μM) andpercentage of cell viability at 24 hours.

FIG. 8 shows structures of PTL (1), DMAPT fumarate (2) and MMB (3).

FIG. 9 shows the cytotoxic mechanism of action of MMB analogs.

FIG. 10 shows a graph demonstrating the anti-leukemic activity ofcarbamate and carbonate derivatives of melampomagnolide B against M9 ENLcells.

FIG. 11 shows a graph demonstrating the anti-leukemic activity ofsuccinic amide derivatives of melampomagnolide B against M9 ENL cells.

DETAILED DESCRIPTION OF THE INVENTION

Provided herein are carbamate, thiocarbamate, and carbonate conjugatesof MMB, which may be synthesized via an intermediate prepared byreacting MMB with carbonylditriazole to afford MMB triazole (JVM 2-16,Example 10). This triazole intermediate may be reacted with variousheterocyclic amines, including, for example, imidazole, morpholine,piperidine, pyrrolidine, triazole, and pyridine, to afford thecorresponding carbamate conjugate. To prepare carbonate conjugates ofMMB, MMB triazole may be reacted with hydroxyl-containing compounds,including methanol, ethanol, N,N-dimethylethanolamine,morpholinoethanol, and piperidinopropanol. A thiocarbamate conjugate(JVM-66, Example 6) may be synthesized by reacting MMB withthiocarbonyldiimidazole. Also provided herein are carbamate andcarbonate conjugates of MMB, which may be synthesized via anintermediate prepared by reacting MMB with p-nitrophenylchloroformate toafford an ester of MMB. This ester derivative may be reacted withvarious heterocyclic amines, including, for example, imidazole,morpholine, piperidine, pyrrolidine, triazole, and pyridine, orhydroxyl-containing compounds, including methanol, ethanol,N,N-dimethylethanolamine, morpholinoethanol, and piperidinopropanol toafford the corresponding carbamate or carbonate conjugate.

These compounds were tested for anticancer activity against primary andnon-primary AML cell lines and various solid tumor cell lines. Severalcompounds were efficient anticancer agents against the AML cell linesand various solid tumor cell lines.

In general, the compounds detailed herein include compounds comprising amelampomagnolide B (MMB) structure as diagrammed below. For the purposesof illustration, the ring atoms of MMB are numbered as shown below:

MMB compounds have asymmetric centers. In particular, the MMB compoundsmay have at least four chiral carbons (designated by asterisks in thediagram above); namely, C4, C5, C6, and C7.

I. Compounds Comprising Formula (I) or (II)

Provided herein are a compound comprising Formula (I) or (II):

wherein:

-   -   X is O or S;    -   R¹ and R² are independently selected from the group consisting        of —NR³R⁴, —OR³, —O-alkyl-NR³R⁴, —SR³, —S-alkyl-NR³R⁴,        alkyl-C(O)NR³R⁴, and -alkyl-R⁵;    -   R³ is selected from the group consisting of hydrocarbyl,        substituted hydrocarbyl, and R⁵;    -   R⁴ is selected from the group consisting of hydrogen,        hydrocarbyl, and substituted hydrocarbyl;    -   R⁵ is an optionally substituted nitrogen-containing heterocyclic        ring; one or more of R³ and R⁴ may form part of a ring or ring        system chosen from the group consisting of heterocyclic,        substituted heterocyclic, and combinations thereof; and    -   when R⁴ is hydrogen, R³ is selected from the group consisting of        alkyl, R⁵, and substituted hydrocarbyl having at least one        hydroxyl or R⁵.

In an exemplary embodiment of a compound comprising Formula (I), X is O;R¹ is NR³R⁴; and R³, R⁴ and R⁵ are as described above.

In some embodiments, R¹ and R² may be selected from the group consistingof alkoxy, alkylamino, dialkylamino, dialkylaminoalkoxy,heterocyclylalkoxy, hydroxyalkylamino, heterocyclylamino, andheterocyclylalkylamino. In some exemplary embodiments, R¹ and R² may beselected from the group consisting of methylamino, dimethylamino,hydroxyhexylamino, hydroxyethylamino, pyrrolyl, pyrrolidinyl, pyridinyl,piperdinyl, pyrazinyl, piperazinyl, pyrimidinyl, imidazolyl, triazolyl,hydroxypiperdinyl, difluoropiperdinyl, triazolylamino,methylthiotriazolylamino, morpholinyl, morpholinylethylamino,pyridinylmethylamino, piperdinylethylamino, pyridinylethylamino,morpholinylpropylamino, imidiazolylpropylamino, methoxy,dimethylaminoethoxy, piperdinylpropoxy, piperdinylethoxy,pyrrolidinylethoxy, morpholinylethyoxy,piperidinylethoxyhydroxyethylthio, and piperdinylethyl. In otherexemplary embodiments, R¹ and R² may be independently selected from thegroup consisting of imidazolylpropylaminocarbonylethylcarbonyl,difluoropiperinylcarbonylethylcarbonyl,methylthiotriazolylaminocarbonylethylcarbonyl,chloropyridinylmethylaminocarbonylethylcarbonyl,methylpiperdinylcarbonylethylcarbonyl, andmethylpiperazinylcarbonylethylcarbonyl. In a particular embodiment, R¹may be R⁵, and R² may be dialkylamino. In still other embodiments, oneor more R¹, R², R³, R⁴, or R⁵ may be substituted with at least oneselected from the group consisting of methyl, ethyl, propyl, cyano,C₁-C₃-alkylamino, carboxyl, hydroxyl, trifluoromethyl, thio, alkylthio,and halogen.

(a) Downstream Applications

In some embodiments, the compound comprising Formula (I) or (II) may beconverted into a pharmaceutically acceptable salt. “Pharmaceuticallyacceptable salts” are salts commonly used to form alkali metal salts andto form addition salts of free acids or free bases. The nature of thesalt may vary, provided that it is pharmaceutically acceptable.

Suitable pharmaceutically acceptable acid addition salts of compoundscomprising Formula (I) or (II) may be prepared from an inorganic acid orfrom an organic acid. Examples of such inorganic acids are hydrochloric,hydrobromic, hydroiodic, nitric, carbonic, sulfuric and phosphoric acid.Appropriate organic acids may be selected from aliphatic,cycloaliphatic, aromatic, araliphatic, heterocyclic, carboxylic andsulfonic classes of organic acids, examples of which are formic, acetic,propionic, succinic, glycolic, gluconic, lactic, malic, tartaric,citric, ascorbic, glucuronic, maleic, fumaric, pyruvic, aspartic,glutamic, benzoic, anthranilic, mesylic, 4-hydroxybenzoic, phenylacetic,mandelic, embonic (pamoic), methanesulfonic, ethanesulfonic,benzenesulfonic, pantothenic, 2-hydroxyethanesulfonic, toluenesulfonic,sulfanilic, cyclohexylaminosulfonic, stearic, algenic, hydroxybutyric,salicylic, galactaric and galacturonic acid. Suitable pharmaceuticallyacceptable base addition salts include metallic salts made fromaluminum, calcium, lithium, magnesium, potassium, sodium and zinc ororganic salts made from N,N′-dibenzylethylenediamine, chloroprocaine,choline, diethanolamine, ethylenediamine, meglumine-(N-methylglucamine)and procaine. All of these salts may be prepared by conventional meansfrom the corresponding compound by reacting, for example, theappropriate acid or base with the any compound comprising Formula (I) or(II).

(b) Stereochemistry

The compounds comprising Formulas (I) and (II) may independently have anoptical activity of (−) or (+). In particular, the configuration of C4,C5, C6, and C7, respectively, may be RRRR, RRSR, RRRS, RRSS, RSRR, RSSR,RSRS, RSSS, SRRR, SRSR, SRRS, SRSS, SSRR, SSSR, SSRS, or SSSS. Theconfiguration of C4, C5, C6, and C7 may be as shown in Formulas (Ia) and(IIa):

II. Processes for Preparing Compounds Comprising Formula (I) or (II)

In particular, provided herein are processes for preparing a compoundcomprising Formula (I) or (II). In general, the process comprisescontacting MMB with an appropriate reagent to form a compound comprisingFormula (I) or (II).

In an aspect, provided herein are processes for preparing a compoundcomprising Formula (I) or (II). The process comprises (a) contacting MMBwith a triazole reagent to form a triazole intermediate. The processcontinues with (b) contacting the triazole intermediate with a compoundcomprising formula R¹—H to form a compound comprising Formula (I) or(II).

In another aspect, provided herein are processes for preparing acarbamate or carbonate compound comprising Formula (I). The processcomprises (a) contacting MMB with p-nitrophenylchloroformate to form anester derivative of MMB. The process continues with (b) contacting theester derivative of MMB with a compound comprising formula R¹—H to forma compound comprising Formula (I).

In still another aspect, provided herein are processes for preparing anamide compound comprising Formula (I). The process comprises (a)contacting MMB with an acid anhydride to form a carboxylic acidderivative. The process continues with (b) contacting the carboxylicacid derivative with a compound comprising formula R¹—H to form acompound comprising Formula (I).

(a) Carbamate and Carbonate Derivatives of MMB via a TriazoleIntermediate

Carbamate derivatives may be synthesized using, for example, phosgene,acid chlorides, carbamoyl chloride, or 1,1-carbonyldiimidazole (CDI). Insome embodiments, CDI may form a carbamate ester on MMB. CDIadvantageously provides easy handling, low expense, and relatively lowtoxicity. In particular embodiments, imidazole carboxylic esters may beformed by reaction of CDI with MMB. In this reaction imidazole, while abyproduct, also participated in an unexpected Michael addition reactionwith the MMB exocyclic double bond of the carbamate product (Scheme 1).

Thiocarbamate derivatives of MMB may be formed by reacting MMB withthiocarbonyl diimidazole dissolved in dichloromethane. If the reactionis maintained for 3-4 h, the major product was the Michael adduct JVM66A. If the reaction is run for a shorter time (e.g., 1 hour), thethiocarbamate (JVM 66) was the major product (Scheme 2). A detailedsynthesis of JVM 66 is provided below at Example 6.

The triazole derivative of MMB (JVM 2-16) was prepared by reacting MMBwith carbonylditriazole (CTD) dissolved in dichloromethane. The triazolebyproduct does not participate in a Michael addition reaction becausetriazole has only weak nucleophilic properties. The triazoleintermediate (JVM 2-16) reacted with various heterocyclic amines andalcohols to form a variety of carbamate and carbonate derivatives(Scheme 3). A detailed synthesis of JVM 2-16 is provided below atExample 10.

In still other embodiments, the triazole intermediate (JVM 2-16) may bereacted with mercaptoethanol in the presence of triethylamine to affordJVM 2-41. A detailed synthesis of JVM 2-41 is provided below at Example15.

In particular, provided herein are processes for preparing a compoundcomprising Formula (I) or (II). The process comprises (a) contacting acompound comprising Formula (III) with a triazole reagent to form acompound comprising Formula (IV). The process continues with (b)contacting the compound of Formula (IV) with a compound comprisingformula R¹—H to form a compound comprising Formula (I) or (II). Thisprocess is illustrated according to the following reaction scheme:

wherein:

-   -   X is O or S;    -   R¹ is selected from the group consisting of —NR³R⁴, —OR³,        —O-alkyl-NR³R⁴, —SR³, —S-alkyl-NR³R⁴, alkyl-C(O)NR³R⁴, and        -alkyl-R⁵;    -   R³ is selected from the group consisting of hydrocarbyl,        substituted hydrocarbyl, and R⁵;    -   R⁴, R⁶, and R⁷ are independently selected from the group        consisting of hydrogen, hydrocarbyl, and substituted        hydrocarbyl;    -   R⁵ is an optionally substituted nitrogen-containing heterocyclic        ring;    -   one or more of R³ and R⁴ may form part of a ring or ring system        chosen from the group consisting of heterocyclic, substituted        heterocyclic, and combinations thereof; and    -   when R⁴ is hydrogen, R³ is selected from the group consisting of        alkyl, R⁵, and substituted hydrocarbyl having at least one        hydroxyl or R⁵.        (i) Step (a)—Reaction Mixture

Step (a) of the process comprises contacting a compound comprisingFormula (III) with a triazole reagent to form a compound comprisingFormula (IV). The process commences with the formation of a reactionmixture comprising the compound comprising Formula (III), which isdetailed above, the triazole reagent, and optionally a solvent system.

The triazole reagent may be any compound which reacts with a hydroxylgroup to provide a triazolyl carbamate, such as a compound comprisingFormula (IV). Non-limiting examples of suitable triazole reagentsinclude carbonylditriazole (such as 1,1′-carbonyl-di-(1,2,4-triazole)and thiocarbonylditriazole. Another possible synthetic approach to thesynthesis of the imidazole carbamate analog of MMB is by utilizingcarbonyldiimidazole as a reagent instead of carbonylditriazole.

The amounts of triazole reagent that are contacted with the compoundcomprising Formula (III) may vary. In general, the mole to mole ratio ofthe compound comprising Formula (III) to triazole agent may range fromabout 1:0.2 to about 1:15. In certain embodiments, the mole to moleratio of the compound comprising Formula (III) to the triazole reagentmay range from about 1:0.2 to about 1:0.7, from about 1:0.7 to about1:1.5, from about 1:1.5 to about 1:2.5, from about 1:2.5 to about 1:5,from about 1:5 to about 1:10, or from about 1:10 to about 1:15. Incertain embodiments, the mole to mole ratio of the compound comprisingFormula (III) to the triazole reagent may range from about 1:0.7 toabout 1:3.

The reaction is generally conducted in the presence of a solvent orsolvent system. The solvent may be a polar aprotic solvent, a polarprotic solvent, or a nonpolar solvent. Non-limiting examples of suitablepolar aprotic solvents include acetone, acetonitrile, diethoxymethane,N,N-dimethylformamide (DMF), dimethyl sulfoxide (DMSO),N,N-dimethylpropanamide (or dimethylpropionamide; DMP),1,3-dimethyl-3,4,5,6-tetrahydro-2(1H)-pyrimidinone (DMPU),1,3-dimethyl-2-imidazolidinone (DMI), 1,2-dimethoxyethane (DME),dimethoxymethane, bis(2-methoxyethyl)ether, N,N-dimethylacetamide (DMA),N-methyl-2-pyrrolidinone (NMP), 1,4-dioxane, ethyl formate, formamide,hexachloroacetone, hexamethylphosphoramide, methyl acetate,N-methylacetamide, N-methylformamide, methylene chloride(dichloromethane, DCM), chloroform, methoxyethane, morpholine,nitrobenzene, nitromethane, propionitrile, pyridine, sulfolane,tetramethylurea, tetrahydrofuran (THF), 2-methyl tetrahydrofuran,tetrahydropyran, trichloromethane, and combinations thereof.Non-limiting examples of suitable polar protic solvents include water;alcohols such as methanol, ethanol, isopropanol, n-propanol, isobutanol,n-butanol, s-butanol, t-butanol, and the like; diols such as propyleneglycol; organic acids such as formic acid, acetic acid, and so forth;amides such as formamide, acetamide, and the like; and combinations ofany of the above. Representative nonpolar solvents include, but are notlimited to, alkane and substituted alkane solvents (includingcycloalkanes), aromatic hydrocarbons, esters, ethers, ketones, andcombinations thereof. Specific polar aprotic solvents that may beemployed include, for example, dichloromethane, chloroform, andcombinations thereof.

In general, the volume to mass ratio of the solvent to the compoundcomprising Formula (III) ranges from about 1:1 to about 100:1. Invarious embodiments, the volume to mass ratio of the solvent to thecompound comprising Formula (III) may range from about 1:1 to about 5:1,from about 5:1 to about 10:1, from about 10:1 to about 20:1, from about20:1 to about 30:1, from about 30:1 to about 40:1, from about 40:1 toabout 50:1, from about 50:1 to about 60:1, from about 60:1 to about70:1, from about 70:1 to about 80:1, from about 80:1 to about 90:1, orfrom about 90:1 to about 100:1. In exemplary embodiments, the volume tomass ratio of the solvent to the compound comprising Formula (III) mayrange from about 20:1 to about 30:1.

(ii) Step (a)—Reaction Conditions

In general, the reaction is conducted at a temperature that ranges fromabout 0° C. to about 50° C. In various embodiments, the reaction may beconducted at a temperature from about 0° C. to about 10° C., from about10° C. to about 20° C., from about 20° C. to about 30° C., from about30° C. to about 40° C., or from about 40° C. to about 50° C. In certainembodiments, the reaction may be conducted at a temperature of about 25°C. The reaction generally is conducted in an inert atmosphere (e.g.,under nitrogen or argon) and under ambient pressure.

Typically, the reaction is allowed to proceed for a sufficient period oftime until the reaction is complete, as determined by chromatography(e.g., TLC, HPLC) or another suitable method. In this context, a“completed reaction” generally means that the reaction mixture containsa significantly diminished amount of the compound comprising Formula(III), and a significantly increased amount of the compound comprisingFormula (IV) compared to the amounts of each present at the beginning ofthe reaction. Typically, the amount of the compound comprising Formula(III) remaining in the reaction mixture after the reaction is completemay be less than about 3%, or less than about 1%. In general, thereaction may proceed for about 5 minutes to about 48 hours. Typically,the duration of the reaction is longer at lower reaction temperatures.In certain embodiments, the reaction may be allowed to proceed for abouta period of time ranging from about 5 minutes to about 10 minutes, fromabout 10 minutes to about 15 minutes, from about 15 minutes to about 30minutes, from about 30 minutes to about 1 hour, about 1 hour to about 3hours, from about 3 hours to about 6 hours, from about 6 hours to about12 hours, from about 12 hours to about 18 hours, from about 18 hours toabout 24 hours, from about 24 hours to about 36 hours, or from about 36hours to about 48 hours. In certain embodiments, the reaction may beallowed to proceed about 5 minutes to about 15 minutes. In otherembodiments, the reaction may be allowed to proceed about 45 minutes toabout 75 minutes. In still other embodiments, the reaction may beallowed to proceed about 18 hours to about 36 hours.

Generally, the compound comprising Formula (IV) is not isolated and step(b) of the process proceeds in the same reaction pot or reactor. In someembodiments, the compound comprising Formula (IV) may be isolated fromthe reaction mixture using techniques known to those of skill in theart. Non-limiting examples of suitable techniques include precipitation,extraction, evaporation, distillation, chromatography, andcrystallization.

The yield of the compound comprising Formula (IV) can and will vary.Typically, the yield of the compound comprising Formula (IV) may be atleast about 40%. In one embodiment, the yield of the compound comprisingFormula (IV) may range from about 40% to about 60%. In anotherembodiment, the yield of the compound comprising Formula (IV) may rangefrom about 60% to about 80%. In a further embodiment, the yield of thecompound comprising Formula (IV) may range from about 80% to about 90%.In still another embodiment, the yield of the compound comprisingFormula (IV) may be greater than about 90%, or greater than about 95%.

(iii) Step (b)—Reaction Mixture

Step (b) of the process continues with (b) contacting the compound ofFormula (IV) with a compound comprising formula R¹—H to form a compoundcomprising Formula (I). The process commences with the formation of areaction mixture comprising the compound comprising Formula (IV), whichis detailed above, a compound comprising the formula R¹—H, andoptionally a solvent system.

In some embodiments, the compound comprising formula R¹—H may beselected from the group consisting of imidazole, benzimidazole,morpholine, piperidine, pyrrole, pyrrolidine, triazole, tetrazole,piperazine, pyridine, pyrazoloimidazole, methanol, ethanol,N,N-dimethylethanolamine, morpholinoethanol, and piperidinopropanol.

The amounts of the compound comprising formula R¹—H that are contactedwith the compound comprising Formula (IV) may vary. In general, the moleto mole ratio of the compound comprising Formula (IV) to the compoundcomprising formula R¹—H may range from about 1:0.2 to about 1:15. Incertain embodiments, the mole to mole ratio of the compound comprisingFormula (IV) to the compound comprising formula R¹—H may range fromabout 1:0.2 to about 1:0.7, from about 1:0.7 to about 1:1.5, from about1:1.5 to about 1:2.5, from about 1:2.5 to about 1:5, from about 1:5 toabout 1:10, or from about 1:10 to about 1:15. In certain embodiments,the mole to mole ratio of the compound comprising Formula (IV) to thecompound comprising formula R¹—H may range from about 1:0.7 to about1:3.

Contact with the compound comprising formula R¹—H generally is conductedin the presence of a solvent or solvent system. Suitable solvents aredetailed above in Section II(a)(i). In exemplary embodiments, thesolvent may be dichloromethane, chloroform, or combinations thereof. Ingeneral, the volume to mass ratio of the solvent to the compoundcomprising Formula (IV) ranges from about 1:1 to about 100:1. In variousembodiments, the volume to mass ratio of the solvent to the compoundcomprising Formula (IV) may range from about 1:1 to about 5:1, fromabout 5:1 to about 10:1, from about 10:1 to about 20:1, from about 20:1to about 30:1, from about 30:1 to about 40:1, from about 40:1 to about50:1, from about 50:1 to about 60:1, from about 60:1 to about 70:1, fromabout 70:1 to about 80:1, from about 80:1 to about 90:1, or from about90:1 to about 100:1. In exemplary embodiments, the volume to mass ratioof the solvent to the compound comprising Formula (IV) may range fromabout 20:1 to about 30:1.

(iv) Step (b)—Reaction Conditions

In general, the reaction is conducted at a temperature that ranges fromabout 0° C. to about 50° C. In various embodiments, the reaction may beconducted at a temperature from about 0° C. to about 10° C., from about10° C. to about 20° C., from about 20° C. to about 30° C., from about30° C. to about 40° C., or from about 40° C. to about 50° C. In certainembodiments, the reaction may be conducted at a temperature of about 25°C. The reaction generally is conducted in an inert atmosphere (e.g.,under nitrogen or argon) and under ambient pressure.

Typically, the reaction is allowed to proceed for a sufficient period oftime until the reaction is complete, as determined by chromatography(e.g., TLC, HPLC) or another suitable method. Typically, the amount ofthe compound comprising Formula (IV) remaining in the reaction mixtureafter the reaction is complete may be less than about 3%, or less thanabout 1%. In general, the reaction may proceed for about 5 minutes toabout 48 hours. Typically, the duration of the reaction is longer atlower reaction temperatures. In certain embodiments, the reaction may beallowed to proceed for about a period of time ranging from about 5minutes to about 10 minutes, from about 10 minutes to about 15 minutes,from about 15 minutes to about 30 minutes, from about 30 minutes toabout 1 hour, about 1 hour to about 3 hours, from about 3 hours to about6 hours, from about 6 hours to about 12 hours, from about 12 hours toabout 18 hours, from about 18 hours to about 24 hours, from about 24hours to about 36 hours, or from about 36 hours to about 48 hours. Incertain embodiments, the reaction may be allowed to proceed about 20minutes to about 40 minutes. In other embodiments, the reaction may beallowed to proceed about 8 hours to about 12 hours.

The yield of the compound comprising Formula (I) or (II) can and willvary. Typically, the yield of the compound comprising Formula (I) or(II) may be at least about 40%. In one embodiment, the yield of thecompound comprising Formula (I) or (II) may range from about 40% toabout 60%. In another embodiment, the yield of the compound comprisingFormula (I) or (II) may range from about 60% to about 80%. In a furtherembodiment, the yield of the compound comprising Formula (I) or (II) mayrange from about 80% to about 90%. In still another embodiment, theyield of the compound comprising Formula (I) or (II) may be greater thanabout 90%, or greater than about 95%.

(b) Carbamate and Carbonate Derivatives of MMB via an Ester Derivative

In still yet other embodiments, MMB (3) may be reacted withp-nitrophenylchloroformate (4) in the presence of triethylamine to fromthe p-nitrophenyloxycarbonyl ester of MMB (5). Thep-nitrophenyloxycarbonyl ester of MMB may then be reacted with variousprimary and secondary heterocyclic amines to afford carbamate analogs ofMMB (6) (Scheme 4).

In particular, provided herein are processes for preparing a carbamateor carbonate compound comprising Formula (I). The process comprises (a)contacting MMB (2) with p-nitrophenylchloroformate to form an esterderivative of MMB (e.g. (5)). The process continues with (b) contactingthe ester derivative of MMB with a compound comprising formula R¹—H toform a compound comprising Formula (I).

(i) Step (a)—Reaction Mixture

Step (a) of the process comprises contacting MMB withp-nitrophenylchloroformate to form an ester derivative of MMB (e.g.(5)). The process commences with the formation of a reaction mixturecomprising MMB, which is detailed above, p-nitrophenylchloroformate, andoptionally a solvent system.

The amounts of p-nitrophenylchloroformate that are contacted with MMBmay vary. In general, the mole to mole ratio of MMB top-nitrophenylchloroformate may range from about 1:0.2 to about 1:15. Incertain embodiments, the mole to mole ratio of MMB top-nitrophenylchloroformate may range from about 1:0.2 to about 1:0.7,from about 1:0.7 to about 1:1.5, from about 1:1.5 to about 1:2.5, fromabout 1:2.5 to about 1:5, from about 1:5 to about 1:10, or from about1:10 to about 1:15. In certain embodiments, the mole to mole ratio ofMMB to p-nitrophenylchloroformate may range from about 1:0.7 to about1:3. In an exemplary embodiment, the mole to mole ratio of MMB top-nitrophenylchloroformate may be about 1:0.7.

The reaction is generally conducted in the presence of a solvent orsolvent system. The solvent may be a polar aprotic solvent, a polarprotic solvent, or a nonpolar solvent. Non-limiting examples of suitablepolar aprotic solvents include acetone, acetonitrile, diethoxymethane,N,N-dimethylformamide (DMF), dimethyl sulfoxide (DMSO),N,N-dimethylpropanamide (or dimethylpropionamide; DMP),1,3-dimethyl-3,4,5,6-tetrahydro-2(1H)-pyrimidinone (DMPU),1,3-dimethyl-2-imidazolidinone (DMI), 1,2-dimethoxyethane (DME),dimethoxymethane, bis(2-methoxyethyl)ether, N,N-dimethylacetamide (DMA),N-methyl-2-pyrrolidinone (NMP), 1,4-dioxane, ethyl formate, formamide,hexachloroacetone, hexamethylphosphoramide, methyl acetate,N-methylacetamide, N-methylformamide, methylene chloride(dichloromethane, DCM), chloroform, methoxyethane, morpholine,nitrobenzene, nitromethane, propionitrile, pyridine, sulfolane,tetramethylurea, tetrahydrofuran (THF), 2-methyl tetrahydrofuran,tetrahydropyran, trichloromethane, and combinations thereof.Non-limiting examples of suitable polar protic solvents include water;alcohols such as methanol, ethanol, isopropanol, n-propanol, isobutanol,n-butanol, s-butanol, t-butanol, and the like; diols such as propyleneglycol; organic acids such as formic acid, acetic acid, and so forth;amides such as formamide, acetamide, and the like; and combinations ofany of the above. Representative nonpolar solvents include, but are notlimited to, alkane and substituted alkane solvents (includingcycloalkanes), aromatic hydrocarbons, esters, ethers, ketones, andcombinations thereof. Specific polar aprotic solvents that may beemployed include, for example, dichloromethane, chloroform, andcombinations thereof.

A proton acceptor is generally added to facilitate the reaction. Theproton acceptor generally has a pKa greater than about 7, or from about7 to about 13, or more specifically from about 9 to about 11.Representative proton acceptors may include, but are not limited to,borate salts (such as, for example, NaBO₃), di- and tri-basic phosphatesalts, (such as, for example, Na₂HPO₄ and NaPO₄), bicarbonate salts,carbonate salts, hydroxides, alkoxides, (including methoxide, ethoxide,propoxide, butoxide, and pentoxide, including straight chain andbranched), and organic proton acceptors, (such as, for example,pyridine, triethylamine, N-methylmorpholine, andN,N-dimethylaminopyridine), and mixtures thereof. In some embodiments,the proton acceptor may be stabilized by a suitable counterion such aslithium, potassium, sodium, calcium, magnesium, and the like. In aspecific embodiment, the proton acceptor is triethylamine. The amount ofproton acceptor included in the reaction can and will vary, but can bereadily determined by a person of ordinary skill in the art.

In general, the volume to mass ratio of the solvent to MMB ranges fromabout 1:1 to about 100:1. In various embodiments, the volume to massratio of the solvent to MMB may range from about 1:1 to about 5:1, fromabout 5:1 to about 10:1, from about 10:1 to about 20:1, from about 20:1to about 30:1, from about 30:1 to about 40:1, from about 40:1 to about50:1, from about 50:1 to about 60:1, from about 60:1 to about 70:1, fromabout 70:1 to about 80:1, from about 80:1 to about 90:1, or from about90:1 to about 100:1. In exemplary embodiments, the volume to mass ratioof the solvent to MMB may range from about 20:1 to about 30:1. In otherexemplary embodiments, the volume to mass ratio of the solvent to MMBmay range from about 10:1 to about 20:1.

(ii) Step (a)—Reaction Conditions

In general, the reaction is conducted at a temperature that ranges fromabout 0° C. to about 50° C. In various embodiments, the reaction may beconducted at a temperature from about 0° C. to about 10° C., from about10° C. to about 20° C., from about 20° C. to about 30° C., from about30° C. to about 40° C., or from about 40° C. to about 50° C. In certainembodiments, the reaction may be conducted at a temperature of about 25°C. The reaction generally is conducted in an inert atmosphere (e.g.,under nitrogen or argon) and under ambient pressure.

Typically, the reaction is allowed to proceed for a sufficient period oftime until the reaction is complete, as determined by chromatography(e.g., TLC, HPLC) or another suitable method. In this context, a“completed reaction” generally means that the reaction mixture containsa significantly diminished amount of MMB, and a significantly increasedamount of the carboxylic acid derivative compared to the amounts of eachpresent at the beginning of the reaction. Typically, the amount of MMBremaining in the reaction mixture after the reaction is complete may beless than about 3%, or less than about 1%. In general, the reaction mayproceed for about 5 minutes to about 48 hours. Typically, the durationof the reaction is longer at lower reaction temperatures. In certainembodiments, the reaction may be allowed to proceed for about a periodof time ranging from about 5 minutes to about 10 minutes, from about 10minutes to about 15 minutes, from about 15 minutes to about 30 minutes,from about 30 minutes to about 1 hour, about 1 hour to about 3 hours,from about 3 hours to about 6 hours, from about 6 hours to about 12hours, from about 12 hours to about 18 hours, from about 18 hours toabout 24 hours, from about 24 hours to about 36 hours, or from about 36hours to about 48 hours. In certain embodiments, the reaction may beallowed to proceed about 5 minutes to about 15 minutes. In otherembodiments, the reaction may be allowed to proceed about 45 minutes toabout 75 minutes. In still other embodiments, the reaction may beallowed to proceed about 18 hours to about 36 hours. In an exemplaryembodiment, the reaction may be allowed to proceed about 24 hours.

Generally, the ester derivative is not isolated and step (b) of theprocess proceeds in the same reaction pot or reactor. In someembodiments, the ester derivative may be isolated from the reactionmixture using techniques known to those of skill in the art.Non-limiting examples of suitable techniques include precipitation,extraction, evaporation, distillation, chromatography, andcrystallization.

The yield of the ester derivative can and will vary. Typically, theyield of the ester derivative may be at least about 40%. In oneembodiment, the yield of the ester derivative may range from about 40%to about 60%. In another embodiment, the yield of the ester derivativemay range from about 60% to about 80%. In a further embodiment, theyield of the ester derivative may range from about 80% to about 90%. Instill another embodiment, the yield of the ester derivative may begreater than about 90%, or greater than about 95%.

(iii) Step (b)—Reaction Mixture

Step (b) of the process continues with (b) contacting the esterderivative with a compound comprising formula R¹—H to form a compoundcomprising Formula (I) or (II). The process commences with the formationof a reaction mixture comprising the ester derivative, which is detailedabove, a compound comprising the formula R¹—H, and optionally a solventsystem.

In some embodiments, the compound comprising formula R¹—H may beselected from the group consisting of imidazole, benzimidazole,morpholine, piperidine, pyrrole, pyrrolidine, triazole, tetrazole,piperazine, pyridine, pyrazoloimidazole, methanol, ethanol,N,N-dimethylethanolamine, morpholinoethanol, and piperidinopropanol.

The amounts of the compound comprising formula R¹—H that are contactedwith the ester derivative may vary. In general, the mole to mole ratioof the ester derivative to the compound comprising formula R¹—H mayrange from about 1:0.2 to about 1:15. In certain embodiments, the moleto mole ratio of the ester derivative to the compound comprising formulaR¹—H may range from about 1:0.2 to about 1:0.7, from about 1:0.7 toabout 1:1.5, from about 1:1.5 to about 1:2.5, from about 1:2.5 to about1:5, from about 1:5 to about 1:10, or from about 1:10 to about 1:15. Incertain embodiments, the mole to mole ratio of the ester derivative tothe compound comprising formula R¹—H may range from about 1:0.7 to about1:3. In an exemplary, the mole to mole ratio of the ester derivative tothe compound comprising formula R¹—H may be about 1:1.

Contact with the compound comprising formula R¹—H generally is conductedin the presence of a solvent or solvent system. Suitable solvents aredetailed above in Section II(b)(i). In exemplary embodiments, thesolvent may be dichloromethane, chloroform, or combinations thereof. Ingeneral, the volume to mass ratio of the solvent to the ester derivativeranges from about 1:1 to about 100:1. In various embodiments, the volumeto mass ratio of the solvent to the ester derivative may range fromabout 1:1 to about 5:1, from about 5:1 to about 10:1, from about 10:1 toabout 20:1, from about 20:1 to about 30:1, from about 30:1 to about40:1, from about 40:1 to about 50:1, from about 50:1 to about 60:1, fromabout 60:1 to about 70:1, from about 70:1 to about 80:1, from about 80:1to about 90:1, or from about 90:1 to about 100:1. In exemplaryembodiments, the volume to mass ratio of the solvent to the esterderivative may range from about 20:1 to about 30:1. In another exemplaryembodiment, the volume to mass ratio of the solvent to the esterderivative may range from about 10:1 to about 20:1.

(iv) Step (b)—Reaction Conditions

In general, the reaction is conducted at a temperature that ranges fromabout 0° C. to about 50° C. In various embodiments, the reaction may beconducted at a temperature from about 0° C. to about 10° C., from about10° C. to about 20° C., from about 20° C. to about 30° C., from about30° C. to about 40° C., or from about 40° C. to about 50° C. In certainembodiments, the reaction may be conducted at a temperature of about 25°C. The reaction generally is conducted in an inert atmosphere (e.g.,under nitrogen or argon) and under ambient pressure.

Typically, the reaction is allowed to proceed for a sufficient period oftime until the reaction is complete, as determined by chromatography(e.g., TLC, HPLC) or another suitable method. Typically, the amount ofthe ester derivative remaining in the reaction mixture after thereaction is complete may be less than about 3%, or less than about 1%.In general, the reaction may proceed for about 5 minutes to about 48hours. Typically, the duration of the reaction is longer at lowerreaction temperatures. In certain embodiments, the reaction may beallowed to proceed for about a period of time ranging from about 5minutes to about 10 minutes, from about 10 minutes to about 15 minutes,from about 15 minutes to about 30 minutes, from about 30 minutes toabout 1 hour, about 1 hour to about 3 hours, from about 3 hours to about6 hours, from about 6 hours to about 12 hours, from about 12 hours toabout 18 hours, from about 18 hours to about 24 hours, from about 24hours to about 36 hours, or from about 36 hours to about 48 hours. Incertain embodiments, the reaction may be allowed to proceed about 20minutes to about 40 minutes. In other embodiments, the reaction may beallowed to proceed about 5 hours to about 18 hours. In exemplaryembodiments, the reaction may be allowed to proceed about 5 hours toabout 12 hours.

The yield of the compound comprising Formula (I) or (II) can and willvary. Typically, the yield of the compound comprising Formula (I) or(II) may be at least about 40%. In one embodiment, the yield of thecompound comprising Formula (I) or (II) may range from about 40% toabout 60%. In another embodiment, the yield of the compound comprisingFormula (I) or (II) may range from about 60% to about 80%. In a furtherembodiment, the yield of the compound comprising Formula (I) or (II) mayrange from about 80% to about 90%. In still another embodiment, theyield of the compound comprising Formula (I) or (II) may be greater thanabout 90%, or greater than about 95%.

(c) Amide Derivatives of MMB

In other embodiments, MMB may be reacted with succinic anhydride inpresence of triethylamine to afford a carboxylic acid derivative of MMB,JVM 67. The MMB carboxylic acid derivative may be reacted withheterocyclic amines to afford the corresponding amide derivatives of MMB(Scheme 5). A detailed synthesis of JVM 67 is provided below at Example7.

In particular, provided herein are processes for preparing an amidecompound comprising Formula (I). The process comprises (a) contactingMMB with an acid anhydride to form a carboxylic acid derivative. Theprocess continues with (b) contacting the carboxylic acid derivativewith a compound comprising formula R¹—H to form a compound comprisingFormula (I).

(i) Step (a)—Reaction Mixture

Step (a) of the process comprises contacting MMB with an acid anhydrideto form a carboxylic acid derivative. The process commences with theformation of a reaction mixture comprising MMB, which is detailed above,the acid anhydride, and optionally a solvent system.

The acid anhydride may be any compound which reacts with a hydroxylgroup to provide a carboxylic acid derivative. A suitable acid anhydrideis a compound that has two acyl groups bonded to the same oxygen atom.In a preferred embodiment, the acid anhydride is a cyclic anhydride.Non-limiting examples of suitable acid anhydrides include succinicanhydride, maleic anhydride, itaconic anhydride, citraconic anhydrideand 2-pentendioic anhydride. In an exemplary embodiment, the acidanhydride is succinic anhydride.

The amounts of acid anhydride that are contacted with MMB may vary. Ingeneral, the mole to mole ratio of MMB to acid anhydride may range fromabout 1:0.2 to about 1:15. In certain embodiments, the mole to moleratio of MMB to acid anhydride may range from about 1:0.2 to about1:0.7, from about 1:0.7 to about 1:1.5, from about 1:1.5 to about 1:2.5,from about 1:2.5 to about 1:5, from about 1:5 to about 1:10, or fromabout 1:10 to about 1:15. In certain embodiments, the mole to mole ratioof MMB to acid anhydride may range from about 1:0.7 to about 1:3. In anexemplary embodiment, the mole to mole ratio of MMB to acid anhydridemay range from about 1:1.

The reaction is generally conducted in the presence of a solvent orsolvent system. The solvent may be a polar aprotic solvent, a polarprotic solvent, or a nonpolar solvent. Non-limiting examples of suitablepolar aprotic solvents include acetone, acetonitrile, diethoxymethane,N,N-dimethylformamide (DMF), dimethyl sulfoxide (DMSO),N,N-dimethylpropanamide (or dimethylpropionamide; DMP),1,3-dimethyl-3,4,5,6-tetrahydro-2(1H)-pyrimidinone (DMPU),1,3-dimethyl-2-imidazolidinone (DMI), 1,2-dimethoxyethane (DME),dimethoxymethane, bis(2-methoxyethyl)ether, N,N-dimethylacetamide (DMA),N-methyl-2-pyrrolidinone (NMP), 1,4-dioxane, ethyl formate, formamide,hexachloroacetone, hexamethylphosphoramide, methyl acetate,N-methylacetamide, N-methylformamide, methylene chloride(dichloromethane, DCM), chloroform, methoxyethane, morpholine,nitrobenzene, nitromethane, propionitrile, pyridine, sulfolane,tetramethylurea, tetrahydrofuran (THF), 2-methyl tetrahydrofuran,tetrahydropyran, trichloromethane, and combinations thereof.Non-limiting examples of suitable polar protic solvents include water;alcohols such as methanol, ethanol, isopropanol, n-propanol, isobutanol,n-butanol, s-butanol, t-butanol, and the like; diols such as propyleneglycol; organic acids such as formic acid, acetic acid, and so forth;amides such as formamide, acetamide, and the like; and combinations ofany of the above. Representative nonpolar solvents include, but are notlimited to, alkane and substituted alkane solvents (includingcycloalkanes), aromatic hydrocarbons, esters, ethers, ketones, andcombinations thereof. Specific polar aprotic solvents that may beemployed include, for example, dichloromethane, chloroform, andcombinations thereof.

A proton acceptor is generally added to facilitate the reaction. Theproton acceptor generally has a pKa greater than about 7, or from about7 to about 13, or more specifically from about 9 to about 11.Representative proton acceptors may include, but are not limited to,borate salts (such as, for example, NaBO₃), di- and tri-basic phosphatesalts, (such as, for example, Na₂HPO₄ and NaPO₄), bicarbonate salts,carbonate salts, hydroxides, alkoxides, (including methoxide, ethoxide,propoxide, butoxide, and pentoxide, including straight chain andbranched), and organic proton acceptors, (such as, for example,pyridine, triethylamine, N-methylmorpholine, andN,N-dimethylaminopyridine), and mixtures thereof. In some embodiments,the proton acceptor may be stabilized by a suitable counterion such aslithium, potassium, sodium, calcium, magnesium, and the like. In aspecific embodiment, the proton acceptor is triethylamine. The amount ofproton acceptor included in the reaction can and will vary, but can bereadily determined by a person of ordinary skill in the art.

In general, the volume to mass ratio of the solvent to MMB ranges fromabout 1:1 to about 100:1. In various embodiments, the volume to massratio of the solvent to MMB may range from about 1:1 to about 5:1, fromabout 5:1 to about 10:1, from about 10:1 to about 20:1, from about 20:1to about 30:1, from about 30:1 to about 40:1, from about 40:1 to about50:1, from about 50:1 to about 60:1, from about 60:1 to about 70:1, fromabout 70:1 to about 80:1, from about 80:1 to about 90:1, or from about90:1 to about 100:1. In exemplary embodiments, the volume to mass ratioof the solvent to MMB may range from about 20:1 to about 30:1. In otherexemplary embodiments, the volume to mass ratio of the solvent to MMBmay range from about 10:1 to about 20:1.

(ii) Step (a)—Reaction Conditions

In general, the reaction is conducted at a temperature that ranges fromabout 0° C. to about 50° C. In various embodiments, the reaction may beconducted at a temperature from about 0° C. to about 10° C., from about10° C. to about 20° C., from about 20° C. to about 30° C., from about30° C. to about 40° C., or from about 40° C. to about 50° C. In certainembodiments, the reaction may be conducted at a temperature of about 25°C. The reaction generally is conducted in an inert atmosphere (e.g.,under nitrogen or argon) and under ambient pressure.

Typically, the reaction is allowed to proceed for a sufficient period oftime until the reaction is complete, as determined by chromatography(e.g., TLC, HPLC) or another suitable method. In this context, a“completed reaction” generally means that the reaction mixture containsa significantly diminished amount of MMB, and a significantly increasedamount of the carboxylic acid derivative compared to the amounts of eachpresent at the beginning of the reaction. Typically, the amount of MMBremaining in the reaction mixture after the reaction is complete may beless than about 3%, or less than about 1%. In general, the reaction mayproceed for about 5 minutes to about 48 hours. Typically, the durationof the reaction is longer at lower reaction temperatures. In certainembodiments, the reaction may be allowed to proceed for about a periodof time ranging from about 5 minutes to about 10 minutes, from about 10minutes to about 15 minutes, from about 15 minutes to about 30 minutes,from about 30 minutes to about 1 hour, about 1 hour to about 3 hours,from about 3 hours to about 6 hours, from about 6 hours to about 12hours, from about 12 hours to about 18 hours, from about 18 hours toabout 24 hours, from about 24 hours to about 36 hours, or from about 36hours to about 48 hours. In certain embodiments, the reaction may beallowed to proceed about 5 minutes to about 15 minutes. In otherembodiments, the reaction may be allowed to proceed about 45 minutes toabout 75 minutes. In still other embodiments, the reaction may beallowed to proceed about 36 hours to about 48 hours.

Generally, the carboxylic acid derivative is not isolated and step (b)of the process proceeds in the same reaction pot or reactor. In someembodiments, the carboxylic acid derivative may be isolated from thereaction mixture using techniques known to those of skill in the art.Non-limiting examples of suitable techniques include precipitation,extraction, evaporation, distillation, chromatography, andcrystallization.

The yield of the carboxylic acid derivative can and will vary.Typically, the yield of the carboxylic acid derivative may be at leastabout 40%. In one embodiment, the yield of the carboxylic acidderivative may range from about 40% to about 60%. In another embodiment,the yield of the carboxylic acid derivative may range from about 60% toabout 80%. In a further embodiment, the yield of the carboxylic acidderivative may range from about 80% to about 90%. In still anotherembodiment, the yield of the carboxylic acid derivative may be greaterthan about 90%, or greater than about 95%.

(iii) Step (b)—Reaction Mixture

Step (b) of the process continues with (b) contacting the carboxylicacid derivative with a compound comprising formula R¹—H to form acompound comprising Formula (I). The process commences with theformation of a reaction mixture comprising the carboxylic acidderivative, which is detailed above, a compound comprising the formulaR¹—H, and optionally a solvent system.

In some embodiments, the compound comprising formula R¹—H may beselected from the group consisting of imidazole, benzimidazole,morpholine, piperidine, pyrrole, pyrrolidine, triazole, tetrazole,piperazine, pyridine, pyrazoloimidazole, methanol, ethanol,N,N-dimethylethanolamine, morpholinoethanol, and piperidinopropanol.

The amounts of the compound comprising formula R¹—H that are contactedwith the carboxylic acid derivative may vary. In general, the mole tomole ratio of the carboxylic acid derivative to the compound comprisingformula R¹—H may range from about 1:0.2 to about 1:15. In certainembodiments, the mole to mole ratio of the carboxylic acid derivative tothe compound comprising formula R¹—H may range from about 1:0.2 to about1:0.7, from about 1:0.7 to about 1:1.5, from about 1:1.5 to about 1:2.5,from about 1:2.5 to about 1:5, from about 1:5 to about 1:10, or fromabout 1:10 to about 1:15. In certain embodiments, the mole to mole ratioof the carboxylic acid derivative to the compound comprising formulaR¹—H may range from about 1:0.7 to about 1:3.

Contact with the compound comprising formula R¹—H generally is conductedin the presence of a solvent or solvent system. Suitable solvents aredetailed above in Section II(c)(i). In exemplary embodiments, thesolvent may be dichloromethane, chloroform, or combinations thereof.Additionally, a proton acceptor is generally added to facilitate thereaction. Suitable proton acceptors are detailed above in SectionII(c)(i). In a specific embodiment, the proton acceptor istriethylamine. Further, peptide coupling agents may also be added to thereaction. Non-limiting examples of suitable peptide coupling agentsinclude EDC (1-Ethyl-3-(3-dimethylaminopropyl)carbodiimide)), HOBt(Hydroxybenzotriazole), DCC (N,N′-Dicyclohexylcarbodiimide), HATU((1-[Bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium3-oxid hexafluorophosphate)), HBTU(O-(Benzotriazol-1-yl)-N,N,N′,N′-tetramethyluroniumHexafluorophosphate), and TBTU(O-(Benzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium tetrafluoroborate).In an exemplary embodiment, EDC(1-Ethyl-3-(3-dimethylaminopropyl)carbodiimide)) and HOBt(Hydroxybenzotriazole) are added to the reaction.

In general, the volume to mass ratio of the solvent to the carboxylicacid derivative ranges from about 1:1 to about 100:1. In variousembodiments, the volume to mass ratio of the solvent to the carboxylicacid derivative may range from about 1:1 to about 5:1, from about 5:1 toabout 10:1, from about 10:1 to about 20:1, from about 20:1 to about30:1, from about 30:1 to about 40:1, from about 40:1 to about 50:1, fromabout 50:1 to about 60:1, from about 60:1 to about 70:1, from about 70:1to about 80:1, from about 80:1 to about 90:1, or from about 90:1 toabout 100:1. In exemplary embodiments, the volume to mass ratio of thesolvent to the carboxylic acid derivative may range from about 20:1 toabout 30:1. In another exemplary embodiment, the volume to mass ratio ofthe solvent to the carboxylic acid derivative may range from about 10:1to about 20:1.

(iv) Step (b)—Reaction Conditions

In general, the reaction is conducted at a temperature that ranges fromabout 0° C. to about 50° C. In various embodiments, the reaction may beconducted at a temperature from about 0° C. to about 10° C., from about10° C. to about 20° C., from about 20° C. to about 30° C., from about30° C. to about 40° C., or from about 40° C. to about 50° C. In certainembodiments, the reaction may be conducted at a temperature of about 25°C. In other embodiments, the reaction may be conducted at a temperaturefrom about 0° C. to about 25° C. The reaction generally is conducted inan inert atmosphere (e.g., under nitrogen or argon) and under ambientpressure.

Typically, the reaction is allowed to proceed for a sufficient period oftime until the reaction is complete, as determined by chromatography(e.g., TLC, HPLC) or another suitable method. Typically, the amount ofthe carboxylic acid derivative remaining in the reaction mixture afterthe reaction is complete may be less than about 3%, or less than about1%. In general, the reaction may proceed for about 5 minutes to about 48hours. Typically, the duration of the reaction is longer at lowerreaction temperatures. In certain embodiments, the reaction may beallowed to proceed for about a period of time ranging from about 5minutes to about 10 minutes, from about 10 minutes to about 15 minutes,from about 15 minutes to about 30 minutes, from about 30 minutes toabout 1 hour, about 1 hour to about 3 hours, from about 3 hours to about6 hours, from about 6 hours to about 12 hours, from about 12 hours toabout 18 hours, from about 18 hours to about 24 hours, from about 24hours to about 36 hours, or from about 36 hours to about 48 hours. Incertain embodiments, the reaction may be allowed to proceed about 3hours to about 16 hours.

The yield of the compound comprising Formula (I) or (II) can and willvary. Typically, the yield of the compound comprising Formula (I) or(II) may be at least about 40%. In one embodiment, the yield of thecompound comprising Formula (I) or (II) may range from about 40% toabout 60%. In another embodiment, the yield of the compound comprisingFormula (I) or (II) may range from about 60% to about 80%. In a furtherembodiment, the yield of the compound comprising Formula (I) or (II) mayrange from about 80% to about 90%. In still another embodiment, theyield of the compound comprising Formula (I) or (II) may be greater thanabout 90%, or greater than about 95%.

III. Compositions

The present disclosure also provides pharmaceutical compositions. Thepharmaceutical composition comprises a compound comprising Formulas (I)or (II) which is detailed above in Section I, as an active ingredientand at least one pharmaceutically acceptable excipient.

The pharmaceutically acceptable excipient may be a diluent, a binder, afiller, a buffering agent, a pH modifying agent, a disintegrant, adispersant, a preservative, a lubricant, taste-masking agent, aflavoring agent, or a coloring agent. The amount and types of excipientsutilized to form pharmaceutical compositions may be selected accordingto known principles of pharmaceutical science.

In one embodiment, the excipient may be a diluent. The diluent may becompressible (i.e., plastically deformable) or abrasively brittle.Non-limiting examples of suitable compressible diluents includemicrocrystalline cellulose (MCC), cellulose derivatives, cellulosepowder, cellulose esters (i.e., acetate and butyrate mixed esters),ethyl cellulose, methyl cellulose, hydroxypropyl cellulose,hydroxypropyl methylcellulose, sodium carboxymethylcellulose, cornstarch, phosphated corn starch, pregelatinized corn starch, rice starch,potato starch, tapioca starch, starch-lactose, starch-calcium carbonate,sodium starch glycolate, glucose, fructose, lactose, lactosemonohydrate, sucrose, xylose, lactitol, mannitol, malitol, sorbitol,xylitol, maltodextrin, and trehalose. Non-limiting examples of suitableabrasively brittle diluents include dibasic calcium phosphate (anhydrousor dihydrate), calcium phosphate tribasic, calcium carbonate, andmagnesium carbonate.

In another embodiment, the excipient may be a binder. Suitable bindersinclude, but are not limited to, starches, pregelatinized starches,gelatin, polyvinylpyrrolidone, cellulose, methylcellulose, sodiumcarboxymethylcellulose, ethylcellulose, polyacrylamides,polyvinyloxoazolidone, polyvinylalcohols, C₁₂-C₁₈ fatty acid alcohol,polyethylene glycol, polyols, saccharides, oligosaccharides,polypeptides, oligopeptides, and combinations thereof.

In another embodiment, the excipient may be a filler. Suitable fillersinclude, but are not limited to, carbohydrates, inorganic compounds, andpolyvinylpyrrolidone. By way of non-limiting example, the filler may becalcium sulfate, both di- and tri-basic, starch, calcium carbonate,magnesium carbonate, microcrystalline cellulose, dibasic calciumphosphate, magnesium carbonate, magnesium oxide, calcium silicate, talc,modified starches, lactose, sucrose, mannitol, or sorbitol.

In still another embodiment, the excipient may be a buffering agent.Representative examples of suitable buffering agents include, but arenot limited to, phosphates, carbonates, citrates, tris buffers, andbuffered saline salts (e.g., Tris buffered saline or phosphate bufferedsaline).

In various embodiments, the excipient may be a pH modifier. By way ofnon-limiting example, the pH modifying agent may be sodium carbonate,sodium bicarbonate, sodium citrate, citric acid, or phosphoric acid.

In a further embodiment, the excipient may be a disintegrant. Thedisintegrant may be non-effervescent or effervescent. Suitable examplesof non-effervescent disintegrants include, but are not limited to,starches such as corn starch, potato starch, pregelatinized and modifiedstarches thereof, sweeteners, clays, such as bentonite,micro-crystalline cellulose, alginates, sodium starch glycolate, gumssuch as agar, guar, locust bean, karaya, pecitin, and tragacanth.Non-limiting examples of suitable effervescent disintegrants includesodium bicarbonate in combination with citric acid and sodiumbicarbonate in combination with tartaric acid.

In yet another embodiment, the excipient may be a dispersant ordispersing enhancing agent. Suitable dispersants may include, but arenot limited to, starch, alginic acid, polyvinylpyrrolidones, guar gum,kaolin, bentonite, purified wood cellulose, sodium starch glycolate,isoamorphous silicate, and microcrystalline cellulose.

In another alternate embodiment, the excipient may be a preservative.Non-limiting examples of suitable preservatives include antioxidants,such as BHA, BHT, vitamin A, vitamin C, vitamin E, or retinyl palmitate,citric acid, sodium citrate; chelators such as EDTA or EGTA; andantimicrobials, such as parabens, chlorobutanol, or phenol.

In a further embodiment, the excipient may be a lubricant. Non-limitingexamples of suitable lubricants include minerals such as talc or silica;and fats such as vegetable stearin, magnesium stearate or stearic acid.

In yet another embodiment, the excipient may be a taste-masking agent.Taste-masking materials include cellulose ethers; polyethylene glycols;polyvinyl alcohol; polyvinyl alcohol and polyethylene glycol copolymers;monoglycerides or triglycerides; acrylic polymers; mixtures of acrylicpolymers with cellulose ethers; cellulose acetate phthalate; andcombinations thereof.

In an alternate embodiment, the excipient may be a flavoring agent.Flavoring agents may be chosen from synthetic flavor oils and flavoringaromatics and/or natural oils, extracts from plants, leaves, flowers,fruits, and combinations thereof.

In still a further embodiment, the excipient may be a coloring agent.Suitable color additives include, but are not limited to, food, drug andcosmetic colors (FD&C), drug and cosmetic colors (D&C), or external drugand cosmetic colors (Ext. D&C).

The weight fraction of the excipient or combination of excipients in thecomposition may be about 99% or less, about 97% or less, about 95% orless, about 90% or less, about 85% or less, about 80% or less, about 75%or less, about 70% or less, about 65% or less, about 60% or less, about55% or less, about 50% or less, about 45% or less, about 40% or less,about 35% or less, about 30% or less, about 25% or less, about 20% orless, about 15% or less, about 10% or less, about 5% or less, about 2%,or about 1% or less of the total weight of the composition.

The composition can be formulated into various dosage forms andadministered by a number of different means that will deliver atherapeutically effective amount of the active ingredient. Suchcompositions can be administered orally, parenterally, or topically indosage unit formulations containing conventional nontoxicpharmaceutically acceptable carriers, adjuvants, and vehicles asdesired. Topical administration may also involve the use of transdermaladministration such as transdermal patches or iontophoresis devices. Theterm parenteral as used herein includes subcutaneous, intravenous,intramuscular, or intrasternal injection, or infusion techniques.Formulation of drugs is discussed in, for example, Gennaro, A. R.,Remington's Pharmaceutical Sciences, Mack Publishing Co., Easton, Pa.(18^(th) ed, 1995), and Liberman, H. A. and Lachman, L., Eds.,Pharmaceutical Dosage Forms, Marcel Dekker Inc., New York, N.Y. (1980).

Solid dosage forms for oral administration include capsules, tablets,caplets, pills, powders, pellets, and granules. In such solid dosageforms, the active ingredient is ordinarily combined with one or morepharmaceutically acceptable excipients, examples of which are detailedabove. Oral preparations may also be administered as aqueoussuspensions, elixirs, or syrups. For these, the active ingredient may becombined with various sweetening or flavoring agents, coloring agents,and, if so desired, emulsifying and/or suspending agents, as well asdiluents such as water, ethanol, glycerin, and combinations thereof.

For parenteral administration (including subcutaneous, intradermal,intravenous, intramuscular, and intraperitoneal), the preparation may bean aqueous or an oil-based solution. Aqueous solutions may include asterile diluent such as water, saline solution, a pharmaceuticallyacceptable polyol such as glycerol, propylene glycol, or other syntheticsolvents; an antibacterial and/or antifungal agent such as benzylalcohol, methyl paraben, chlorobutanol, phenol, thimerosal, and thelike; an antioxidant such as ascorbic acid or sodium bisulfite; achelating agent such as etheylenediaminetetraacetic acid; a buffer suchas acetate, citrate, or phosphate; and/or an agent for the adjustment oftonicity such as sodium chloride, dextrose, or a polyalcohol such asmannitol or sorbitol. The pH of the aqueous solution may be adjustedwith acids or bases such as hydrochloric acid or sodium hydroxide.Oil-based solutions or suspensions may further comprise sesame, peanut,olive oil, or mineral oil.

For topical (e.g., transdermal or transmucosal) administration,penetrants appropriate to the barrier to be permeated are generallyincluded in the preparation. Transmucosal administration may beaccomplished through the use of nasal sprays, aerosol sprays, tablets,or suppositories, and transdermal administration may be via ointments,salves, gels, patches, or creams as generally known in the art.

In certain embodiments, a composition comprising a compound of theinvention is encapsulated in a suitable vehicle to either aid in thedelivery of the compound to target cells, to increase the stability ofthe composition, or to minimize potential toxicity of the composition.As will be appreciated by a skilled artisan, a variety of vehicles aresuitable for delivering a composition of the present invention.Non-limiting examples of suitable structured fluid delivery systems mayinclude nanoparticles, liposomes, microemulsions, micelles, dendrimersand other phospholipid-containing systems. Methods of incorporatingcompositions into delivery vehicles are known in the art.

In one alternative embodiment, a liposome delivery vehicle may beutilized. Liposomes, depending upon the embodiment, are suitable fordelivery of the compound of the invention in view of their structuraland chemical properties. Generally speaking, liposomes are sphericalvesicles with a phospholipid bilayer membrane. The lipid bilayer of aliposome may fuse with other bilayers (e.g., the cell membrane), thusdelivering the contents of the liposome to cells. In this manner, thecompound of the invention may be selectively delivered to a cell byencapsulation in a liposome that fuses with the targeted cell'smembrane.

Liposomes may be comprised of a variety of different types ofphosolipids having varying hydrocarbon chain lengths. Phospholipidsgenerally comprise two fatty acids linked through glycerol phosphate toone of a variety of polar groups. Suitable phospholids includephosphatidic acid (PA), phosphatidylserine (PS), phosphatidylinositol(PI), phosphatidylglycerol (PG), diphosphatidylglycerol (DPG),phosphatidylcholine (PC), and phosphatidylethanolamine (PE). The fattyacid chains comprising the phospholipids may range from about 6 to about26 carbon atoms in length, and the lipid chains may be saturated orunsaturated. Suitable fatty acid chains include (common name presentedin parentheses) n-dodecanoate (laurate), n-tretradecanoate (myristate),n-hexadecanoate (palmitate), n-octadecanoate (stearate), n-eicosanoate(arachidate), n-docosanoate (behenate), n-tetracosanoate (lignocerate),cis-9-hexadecenoate (palmitoleate), cis-9-octadecanoate (oleate),cis,cis-9,12-octadecandienoate (linoleate), all cis-9, 12,15-octadecatrienoate (linolenate), and allcis-5,8,11,14-eicosatetraenoate (arachidonate). The two fatty acidchains of a phospholipid may be identical or different. Acceptablephospholipids include dioleoyl PS, dioleoyl PC, distearoyl PS,distearoyl PC, dimyristoyl PS, dimyristoyl PC, dipalmitoyl PG, stearoyl,oleoyl PS, palmitoyl, linolenyl PS, and the like.

The phospholipids may come from any natural source, and, as such, maycomprise a mixture of phospholipids. For example, egg yolk is rich inPC, PG, and PE, soy beans contains PC, PE, PI, and PA, and animal brainor spinal cord is enriched in PS. Phospholipids may come from syntheticsources too. Mixtures of phospholipids having a varied ratio ofindividual phospholipids may be used. Mixtures of differentphospholipids may result in liposome compositions having advantageousactivity or stability of activity properties. The above mentionedphospholipids may be mixed, in optimal ratios with cationic lipids, suchas N-(1-(2,3-dioleolyoxy)propyl)-N,N,N-trimethyl ammonium chloride,1,1′-dioctadecyl-3,3,3′,3′-tetramethylindocarbocyanine perchloarate,3,3′-deheptyloxacarbocyanine iodide,1,1′-dedodecyl-3,3,3′,3′-tetramethylindocarbocyanine perchloarate,1,1′-dioleyl-3,3,3′,3′-tetramethylindo carbocyanine methanesulfonate,N-4-(delinoleylaminostyryl)-N-methylpyridinium iodide, or1,1,-dilinoleyl-3,3,3′,3′-tetramethylindocarbocyanine perchloarate.

Liposomes may optionally comprise sphingolipids, in which spingosine isthe structural counterpart of glycerol and one of the one fatty acids ofa phosphoglyceride, or cholesterol, a major component of animal cellmembranes. Liposomes may optionally, contain pegylated lipids, which arelipids covalently linked to polymers of polyethylene glycol (PEG). PEGsmay range in size from about 500 to about 10,000 daltons.

Liposomes may further comprise a suitable solvent. The solvent may be anorganic solvent or an inorganic solvent. Suitable solvents include, butare not limited to, dimethylsulfoxide (DMSO), methylpyrrolidone,N-methylpyrrolidone, acetronitrile, alcohols, dimethylformamide,tetrahydrofuran, or combinations thereof.

Liposomes carrying the compound of the invention (i.e., having at leastone methionine compound) may be prepared by any known method ofpreparing liposomes for drug delivery, such as, for example, detailed inU.S. Pat. Nos. 4,241,046, 4,394,448, 4,529,561, 4,755,388, 4,828,837,4,925,661, 4,954,345, 4,957,735, 5,043,164, 5,064,655, 5,077,211 and5,264,618, the disclosures of which are hereby incorporated by referencein their entirety. For example, liposomes may be prepared by sonicatinglipids in an aqueous solution, solvent injection, lipid hydration,reverse evaporation, or freeze drying by repeated freezing and thawing.In a preferred embodiment the liposomes are formed by sonication. Theliposomes may be multilamellar, which have many layers like an onion, orunilamellar. The liposomes may be large or small. Continued high-shearsonication tends to form smaller unilamellar lipsomes.

As would be apparent to one of ordinary skill, all of the parametersthat govern liposome formation may be varied. These parameters include,but are not limited to, temperature, pH, concentration of methioninecompound, concentration and composition of lipid, concentration ofmultivalent cations, rate of mixing, presence of and concentration ofsolvent.

In another embodiment, a composition of the invention may be deliveredto a cell as a microemulsion. Microemulsions are generally clear,thermodynamically stable solutions comprising an aqueous solution, asurfactant, and “oil.” The “oil” in this case, is the supercriticalfluid phase. The surfactant rests at the oil-water interface. Any of avariety of surfactants are suitable for use in microemulsionformulations including those described herein or otherwise known in theart. The aqueous microdomains suitable for use in the inventiongenerally will have characteristic structural dimensions from about 5 nmto about 100 nm. Aggregates of this size are poor scatterers of visiblelight and hence, these solutions are optically clear. As will beappreciated by a skilled artisan, microemulsions can and will have amultitude of different microscopic structures including sphere, rod, ordisc shaped aggregates. In one embodiment, the structure may bemicelles, which are the simplest microemulsion structures that aregenerally spherical or cylindrical objects. Micelles are like drops ofoil in water, and reverse micelles are like drops of water in oil. In analternative embodiment, the microemulsion structure is the lamellae. Itcomprises consecutive layers of water and oil separated by layers ofsurfactant. The “oil” of microemulsions optimally comprisesphospholipids. Any of the phospholipids detailed above for liposomes aresuitable for embodiments directed to microemulsions. The composition ofthe invention may be encapsulated in a microemulsion by any methodgenerally known in the art.

In yet another embodiment, a composition of the invention may bedelivered in a dendritic macromolecule, or a dendrimer. Generallyspeaking, a dendrimer is a branched tree-like molecule, in which eachbranch is an interlinked chain of molecules that divides into two newbranches (molecules) after a certain length. This branching continuesuntil the branches (molecules) become so densely packed that the canopyforms a globe. Generally, the properties of dendrimers are determined bythe functional groups at their surface. For example, hydrophilic endgroups, such as carboxyl groups, would typically make a water-solubledendrimer. Alternatively, phospholipids may be incorporated in thesurface of a dendrimer to facilitate absorption across the skin. Any ofthe phospholipids detailed for use in liposome embodiments are suitablefor use in dendrimer embodiments. Any method generally known in the artmay be utilized to make dendrimers and to encapsulate compositions ofthe invention therein. For example, dendrimers may be produced by aniterative sequence of reaction steps, in which each additional iterationleads to a higher order dendrimer. Consequently, they have a regular,highly branched 3D structure, with nearly uniform size and shape.Furthermore, the final size of a dendrimer is typically controlled bythe number of iterative steps used during synthesis. A variety ofdendrimer sizes are suitable for use in the invention. Generally, thesize of dendrimers may range from about 1 nm to about 100 nm.

IV. Methods for Inhibiting Cancer Cell Growth

A further aspect of the present disclosure provides a method forinhibiting growth of a cancer cell. Cancer cell growth includes cellproliferation and cell metastasis. The method comprises contacting thecancer cell with an effective amount of a compound comprising Formulas(I) or (II), or a pharmaceutically acceptable salt thereof, wherein theamount is effective to inhibit growth of the cancer cell. Compoundscomprising Formulas (I) or (II) are detailed above in Section I. In someembodiments, the compound comprising Formulas (I) or (II) is used aspart of a composition, examples of which are detailed above in SectionIII.

(a) Contacting the Cell

In some embodiments, the cancer cell may be in vitro. The cancer cellmay be an established, commercially-available cancer cell line (e.g.,American Type Culture Collection (ATCC), Manassas, Va.). The cancer cellline may be derived from a blood cancer or a solid tumor. The cancercell line may be a human cell line or a mammalian cell line. In aspecific embodiment, the cancer cell line may be derived from a bloodcancer. In one exemplary embodiment, the cancer cell line may be derivedfrom a leukemic cell. The leukemic cell may be an acute myeloid leukemiacell, a chronic myeloid leukemia cell, an acute lymphocytic leukemiacell, a chronic lymphocytic leukemia cell, a cutaneous T cell leukemia,or another type of leukemia cell. In some embodiments, the cancer cellline may be a leukemia cell line such as CCRF-CEM, HL-60(TB), K-562,MOLT-4, RPMI-8226, or SR. In a specific embodiment, the cancer cell linemay be the leukemia cell line CCRF-CEM. In other embodiments, the cancercell line may be a hematopoietic or lymphoid cell line. Non-limitingexamples of hematopoietic or lymphoid cell lines include 380, 697,A3-KAW, A3/KAW, A4-Fuk, A4/Fuk, ALL-PO, ALL-SIL, AML-193, AMO-1, ARH-77,ATN-1, BALL-1, BC-3, BCP-1, BDCM, BE-13, BL-41, BL-70, BV-173, C8166,CA46, CCRF-CEM, CI-1, CMK, CMK-11-5, CMK-86, CML-T1, COLO 775, COLO-677,CTB-1, CTV-1, Daudi, DB, DEL, DG-75, DND-41, DOHH-2, EB1, EB2, EHEB,EJM, EM-2, EOL-1, EoL-1-cell, F-36P, GA-10, GA-10-Clone-4, GDM-1, GR-ST,GRANTA-519, H9, HAL-01, HD-MY-Z, HDLM-2, HEL, HEL 92.1.7, HH, HL-60,HPB-ALL, Hs 604.T, Hs 611.T, Hs 616.T, Hs 751.T, HT, HTK-, HuNS1, HuT102, HuT 78, IM-9, J-RT3-T3-5, JeKo-1, JiyoyeP-2003, JJN-3, JK-1, JM1,JURKAT, JURL-MK1, JVM-2, JVM-3, K-562, K052, KARPAS-299, KARPAS-422,KARPAS-45, KARPAS-620, KASUMI-1, KASUMI-2, Kasumi-6, KCL-22, KE-37,KE-97, KG-1, KHM-1B, Ki-JK, KM-H2, KMM-1, KMOE-2, KMS-11, KMS-12-BM,KMS-12-PE, KMS-18, KMS-20, KMS-21BM, KMS-26, KMS-27, KMS-28BM, KMS-34,KO52, KOPN-8, KU812, KY821, KYO-1, L-1236, L-363, L-428, L-540, LAMA-84,LC4-1, Loucy, LOUCY, LP-1, M-07e, MC-CAR, MC116, ME-1, MEC-1, MEC-2,MEG-01, MHH-CALL-2, MHH-CALL-3, MHH-CALL-4, MHH-PREB-1, Mino, MJ, ML-2,MLMA, MM1-S, MN-60, MOLM-13, MOLM-16, MOLM-6, MOLP-2, MOLP-8, MOLT-13,MOLT-16, MOLT-4, MONO-MAC-1, MONO-MAC-6, MOTN-1, MUTZ-1, MUTZ-3, MUTZ-5,MV-4-11, NALM-1, NALM-19, NALM-6, NAMALWA, NB-4, NCI-H929, NCO2, NKM-1,NOMO-1, NU-DHL-1, NU-DUL-1, OCI-AML2, OCI-AML3, OCI-AML5, OCI-LY-19,OCI-LY10, OCI-LY3, OCI-M1, OPM-2, P12-ICHIKAWA, P30-OHK, P31-FUJ,P31/FUJ, P3HR-1, PCM6, PEER, PF-382, Pfeiffer, PL-21, Raji,Ramos-2G6-4C10, RCH-ACV, REC-1, Reh, REH, RI-1, RL, RPMI 8226,RPMI-8226, RPMI-8402, RS4-11, “RS4; 11”, SEM, Set-2, SIG-M5, SK-MM-2,SKM-1, SR, SR-786, ST486, SU-DHL-1, SU-DHL-10, SU-DHL-4, SU-DHL-5,SU-DHL-6, SU-DHL-8, SUP-B15, SUP-B8, SUP-HD1, SUP-M2, SUP-T1, SUP-T11,TALL-1, TF-1, THP-1, TO 175.T, Toledo, TUR, U-266, U-698-M, U-937,U266B1, UT-7, WSU-DLCL2, and WSU-NHL.

In another exemplary embodiment, the cancer cell line may be derivedfrom a solid tumor cell. The solid tumor cell may be a non-small celllung cancer, colon cancer, CNS cancer, melanoma cancer, ovarian cancer,renal cancer, prostate cancer, breast cancer, or another type of solidtumor cell. In some embodiments, the cancer cell line may be a non-smallcell lung cancer cell line such as A549/ATCC, HOP-92, NCI-H226, NCI-H23,NCI-H322M, NCI-H460, or NCI-H522. In an exemplary embodiment, the cancercell line may be a non-small cell lung cancer cell line such as HOP-92or NCI-H522. In a specific embodiment, the cancer cell line may be thenon-small cell lung cancer cell line HOP-92. In other embodiments, thecancer cell line may be a colon cancer cell line such as COLO 205,HCC-2998, HCT-116, HCT-15, HT29, KM12 or SW-620. In an exemplaryembodiment, the cancer cell line may be a colon cancer cell line such asCOLO 205, HCT-116 or SW-620. In different embodiments, the cancer cellline may be a CNS cancer cell line such as SF-268, SF-295, SF-539,SNB-19, SNB-75 or U251. In an exemplary embodiment, the cancer cell linemay be a CNS cancer cell line such as SF-539 or SNB-75. In some otherembodiments, the cancer cell line may be a melanoma cell line such asLOX IMVI, MALME-3M, M14, MDA-MB-435, SK-MEL-2, SK-MEL-28, SK-MEL-5,UACC-257, or UACC-62. In an exemplary embodiment, the cancer cell linemay be a melanoma cell line such as LOX IMVI, MALME-3M, M14 orMDA-MB-435. In a specific embodiment, the cancer cell line may be themelanoma cell line MDA-MB-435. In still other embodiments, the cancercell line may be an ovarian cancer cell line such as OVCAR-3, OVCAR-4,OVCAR-5, OVCAR-8, NCI/ADR-RES, IGROV1 or SK-OV-3. In an exemplaryembodiment, the cancer cell line may be an ovarian cancer cell line suchas IGROV1 or OVCAR-3. In some different embodiments, the cancer cellline may be a renal cancer cell line such as 786-0, A498, ACHN, CAKI-1,RXF 393, SN12C, TK-10, or UO-31. In an exemplary embodiment, the cancercell line may be a renal cancer cell line such as ACHN, CAKI-1, RXF 393,or TK-10. In a specific embodiment, the cancer cell line may be therenal cancer cell line RXF 393. In other embodiments, the cancer cellline may be a prostate cancer cell line such as PC-3 or DU-145. In anexemplary embodiment, the cancer cell line may be a prostate cancer cellline such as DU-145. In some embodiments, the cancer cell line may be abreast cancer cell line such as MCF7, MDA-BM-231/ATCC, HS 578T, BT-549,T-47D, or MDA-MB-468. In an exemplary embodiment, the cancer cell linemay be a breast cancer cell line such as MCF7, BG-549, T-47D, orMDA-MB-468. In a specific embodiment, the cancer cell line may be thebreast cancer cell line MDA-MB-468.

In other embodiments, the cancer cell may be in vivo; i.e., the cell maybe disposed in a subject. In such embodiments, the cancer cell iscontacted with the compound comprising Formulas (I) or (II) byadministering the compound comprising Formulas (I) or (II) to thesubject. In some embodiments, the subject may be a human. In otherembodiments, the subject may be a non-human animal. Non-limitingexamples of non-human animals include companion animals (e.g., cats,dogs, horses, rabbits, gerbils), agricultural animals (e.g., cows, pigs,sheep, goats, fowl), research animals (e.g., rats, mice, rabbits,primates), and zoo animals (e.g., lions, tiger, elephants, and thelike).

The cancer cell disposed in the subject may be a blood cancer cell(e.g., leukemia, lymphoma, myeloma) or a solid tumor cancer cell. Thecancer may be primary or metastatic; early stage or late stage; and/orthe tumor may be malignant or benign. Non-limiting cancers includebladder cancer, bone cancer, brain cancer, breast cancer, centralnervous system cancer, cervical cancer, colon cancer, colorectal cancer,duodenal cancer, endometrial cancer, esophageal cancer, eye cancer,gallbladder cancer, germ cell cancer, kidney cancer, larynx cancer,leukemia, liver cancer, lymphoma, lung cancer, melanoma, mouth/throatcancer, ovarian cancer, pancreatic cancer, prostate cancer, skin cancer,testicular cancer, thyroid cancer, vaginal cancer, and drug resistantcancers. In one exemplary embodiment, the cancer cell may be a leukemia.The leukemia may be an acute lymphocytic (lymphoblastic) leukemia, achronic lymphocytic leukemia, an acute myeloid leukemia, a chronicmyeloid leukemia, a hairy cell leukemia, a T-cell prolymphocyticleukemia, a large granular lymphocytic leukemia, or an adult T-cellleukemia. In another exemplary embodiment, the cancer cell may be asolid tumor cancer cell selected from the group consisting of non-smallcell lung cancer, colon cancer, CNS cancer, melanoma cancer, ovariancancer, renal cancer, prostate cancer and breast cancer. In a specificembodiment, the cancer cell may be a solid tumor cancer cell selectedfrom the group consisting of non-small cell lung cancer, melanomacancer, renal cancer, and breast cancer.

The compound comprising Formulas (I) or (II) may be administered to thesubject orally (as a solid or a liquid), parenterally (which includesintramuscular, intravenous, intradermal, intraperitoneal, andsubcutaneous), or topically (which includes transmucosal andtransdermal). An effective amount of the compound can be determined by askilled practitioner in view of desired dosages and potential sideeffects of the compound.

The compound comprising Formulas (I) or (II) may be administered once oradministered repeatedly to the subject. Repeated administrations may beat regular intervals of 2 hours, 6 hours, 12 hours, 24 hours, 2 days, 5days, 7 days, 30 days, and so forth.

(b) Inhibiting Cancer Cell Growth

Following contact with an effective amount of the compound comprisingFormulas (I) or (II) growth of the cancer cell is inhibited. Cell growthor proliferation can be measured in cells grown in vitro using standardcell viability or cell cytotoxicity assays (e.g., based on DNA content,cell permeability, etc.) in combination with cell counting methods(e.g., flow cytometry, optical density). Cell growth or proliferationcan be measured in vivo using imaging procedures and/or moleculardiagnostic indicators.

In an embodiment, contact with an effective amount of the compoundcomprising Formulas (I) or (II) selectively inhibits growth of cancercells. As such, a compound comprising Formulas (I) or (II) does notappreciably kill non-cancer cells at the same concentration.Accordingly, more than 50% of non-cancer cells remain viable followingcontact with a compound comprising Formulas (I) or (II) at the sameconcentration. For example about 50%, about 55%, about 60%, about 65%,about 70%, about 75%, about 80%, about 85%, about 90%, about 95% orabout 100% of non-cancer cells remain viable following contact with acompound comprising Formulas (I) or (II) at the same concentration. Or,50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95% or 100% of non-cancercells remain viable following contact with a compound comprisingFormulas (I), (II), (III), (IV) or (V) at the same concentration.

In various embodiments, cancer cell growth may be inhibited about0.5-fold, about 1-fold, about 2-fold, about 3-fold, about 4-fold, about5-fold, about 8-fold, about 10-fold, or more than 10-fold relative to areference value. In various other embodiments, cancer cell growth may beinhibited 0.5-fold, 1-fold, 2-fold, 3-fold, 4-fold, 5-fold, 8-fold,10-fold, or more than 10-fold relative to a reference value. In otherembodiments, cancer cell growth may be inhibited to such a degree thatthe cell undergoes cell death (via apoptosis or necrosis). Any suitablereference value known in the art may be used. For example, a suitablereference value may be cancer cell growth in a sample that has not beencontacted with a compound comprising Formulas (I) or (II). In anotherexample, a suitable reference value may be the baseline growth rate ofthe cells as determined by methods known in the art. In another example,a suitable reference value may be a measurement of the number of cancercells in a reference sample obtained from the same subject. For example,when monitoring the effectiveness of a therapy or efficacy of a compoundcomprising Formulas (I) or (II), a reference sample may be a sampleobtained from a subject before therapy or administration of the compoundcomprising Formulas (I) or (II) began.

(c) Optional Contact

In certain embodiments, the method may further comprise contacting thecell with at least one chemotherapeutic agent and/or a radiotherapeuticagent. The chemotherapeutic agent and/or radiotherapeutic agent may beadministered concurrently or sequentially with the compound comprisingFormulas (I) or (II).

The chemotherapeutic agent may be an alkylating agent, ananti-metabolite, an anti-tumor antibiotic, an anti-cytoskeletal agent, atopoisomerase inhibitor, an anti-hormonal agent, a targeted therapeuticagent, or a combination thereof. Non-limiting examples of suitablealkylating agents include altretamine, benzodopa, busulfan, carboplatin,carboquone, carmustine (BCNU), chlorambucil, chlornaphazine,cholophosphamide, chlorozotocin, cisplatin, cyclosphosphamide,dacarbazine (DTIC), estramustine, fotemustine, ifosfamide, improsulfan,lomustine (CCNU), mechlorethamine, mechlorethamine oxide hydrochloride,melphalan, meturedopa, nimustine, novembichin, phenesterine, piposulfan,prednimustine, ranimustine; temozolomide, thiotepa, triethylenemelamine,trietylenephosphoramide, triethylenethiophosphaoramide,trimethylolomelamine, trofosfamide, uracil mustard and uredopa. Suitableanti-metabolites include, but are not limited to aminopterin,ancitabine, azacitidine, 6-azauridine, capecitabine, carmofur(1-hexylcarbomoyl-5-fluorouracil), cladribine, cytarabine or cytosinearabinoside (Ara-C), dideoxyuridine, denopterin, doxifluridine,enocitabine, floxuridine, fludarabine, 5-fluorouracil, gemcetabine,hydroxyurea, leucovorin (folinic acid), 6-mercaptopurine, methotrexate,pemetrexed, pteropterin, thiamiprine, trimetrexate, and thioguanine.Non-limiting examples of suitable anti-tumor antibiotics includeaclacinomysin, actinomycins, adriamycin, authramycin, azaserine,bleomycins, cactinomycin, calicheamicin, carabicin, caminomycin,carzinophilin, chromomycins, dactinomycin, daunorubicin, detorubicin,6-diazo-5-oxo-L-norleucine, doxorubicin, epirubicin, esorubicin,idarubicin, marcellomycin, mitomycins, mithramycin, mycophenolic acid,nogalamycin, olivomycins, peplomycin, plicamycin, potfiromycin,puromycin, quelamycin, rodorubicin, streptonigrin, streptozocin,tubercidin, valrubicin, ubenimex, zinostatin, and zorubicin.Non-limiting examples of suitable anti-cytoskeletal agents includecolchicines, docetaxel, macromycin, paclitaxel, vinblastine,vincristine, vindesine, and vinorelbine. Suitable topoisomeraseinhibitors include, but are not limited to, amsacrine, etoposide(VP-16), irinotecan, mitoxantrone, RFS 2000, teniposide, and topotecan.Non-limiting examples of suitable anti-hormonal agents such asaminoglutethimide, aromatase inhibiting 4(5)-imidazoles, bicalutamide,finasteride, flutamide, goserelin, 4-hydroxytamoxifen, keoxifene,leuprolide, LY117018, mitotane, nilutamide, onapristone, raloxifene,tamoxifen, toremifene, and trilostane. Examples of targeted therapeuticagents include, without limit, monoclonal antibodies such asalemtuzumab, epratuzumab, gemtuzumab, ibritumomab tiuxetan, rituximab,tositumomab, and trastuzumab; protein kinase inhibitors such asbevacizumab, cetuximab, dasatinib, erlotinib, gefitinib, imatinib,lapatinib, mubritinib, nilotinib, panitumumab, pazopanib, sorafenib,sunitinib, and vandetanib; angiogeneisis inhibitors such as angiostatin,endostatin, bevacizumab, genistein, interferon alpha, interleukin-2,interleukin-12, pazopanib, pegaptanib, ranibizumab, rapamycin,thalidomide; and growth inhibitory polypeptides such as erythropoietin,interleukins (e.g., IL-1, IL-2, IL-3, IL-6), leukemia inhibitory factor,interferons, thrombopoietin, TNF-α, CD30 ligand, 4-1 BB ligand, andApo-1 ligand. Also included are pharmaceutically acceptable salts,acids, or derivatives of any of the above listed agents. The mode ofadministration of the chemotherapeutic agent can and will vary dependingupon the agent and the type of cancer. A skilled practitioner will beable to determine the appropriate dose of the chemotherapeutic agent.

The radiotherapeutic agent may include a radioisotope. Suitableradioisotopes include, without limit, Iodine-131, Iodine-125,Iodine-124, Lutecium-177, Phosphorous-132, Rhenium-186, Strontium-89,Yttrium-90, Iridium-192, and Samarium-153. Alternatively, theradiotherapeutic agent may include a high Z-element chosen from gold,silver, platinum, palladium, cobalt, iron, copper, tin, tantalum,vanadium, molybdenum, tungsten, osmium, iridium, rhenium, hafnium,thallium, lead, bismuth, gadolinium, dysprosium, holmium, and uranium.The appropriate dose of the radiotherapeutic agent may be determined bya skilled practitioner.

DEFINITIONS

The compounds described herein have asymmetric centers. Compounds of thepresent invention containing an asymmetrically substituted atom may beisolated in optically active or racemic form. All chiral,diastereomeric, racemic forms and all geometric isomeric forms of astructure are intended, unless the specific stereochemistry or isomericform is specifically indicated.

The term “acyl,” as used herein alone or as part of another group,denotes the moiety formed by removal of the hydroxy group from the groupCOOH of an organic carboxylic acid, e.g., RC(O)—, wherein R is R¹, R¹O—,R¹R²N—, or R¹S—, R¹ is hydrocarbyl, heterosubstituted hydrocarbyl, orheterocyclo, and R² is hydrogen, hydrocarbyl, or substitutedhydrocarbyl.

The term “acyloxy,” as used herein alone or as part of another group,denotes an acyl group as described above bonded through an oxygenlinkage (O), e.g., RC(O)O— wherein R is as defined in connection withthe term “acyl.”

The term “alkyl” as used herein describes groups which are preferablylower alkyl containing from one to eight carbon atoms in the principalchain and up to 20 carbon atoms. They may be straight or branched chainor cyclic and include methyl, ethyl, propyl, isopropyl, butyl, hexyl andthe like.

The term “alkenyl” as used herein describes groups which are preferablylower alkenyl containing from two to eight carbon atoms in the principalchain and up to 20 carbon atoms. They may be straight or branched chainor cyclic and include ethenyl, propenyl, isopropenyl, butenyl,isobutenyl, hexenyl, and the like.

The term “alkynyl” as used herein describes groups which are preferablylower alkynyl containing from two to eight carbon atoms in the principalchain and up to 20 carbon atoms. They may be straight or branched chainand include ethynyl, propynyl, butynyl, isobutynyl, hexynyl, and thelike.

The term “aromatic” as used herein alone or as part of another groupdenotes optionally substituted homo- or heterocyclic conjugated planarring or ring system comprising delocalized electrons. These aromaticgroups are preferably monocyclic (e.g., furan or benzene), bicyclic, ortricyclic groups containing from 5 to 14 atoms in the ring portion. Theterm “aromatic” encompasses “aryl” groups defined below.

The terms “aryl” or “Ar” as used herein alone or as part of anothergroup denote optionally substituted homocyclic aromatic groups,preferably monocyclic or bicyclic groups containing from 6 to 10 carbonsin the ring portion, such as phenyl, biphenyl, naphthyl, substitutedphenyl, substituted biphenyl, or substituted naphthyl.

The terms “carbocyclo” or “carbocyclic” as used herein alone or as partof another group denote optionally substituted, aromatic ornon-aromatic, homocyclic ring or ring system in which all of the atomsin the ring are carbon, with preferably 5 or 6 carbon atoms in eachring. Exemplary substituents include one or more of the followinggroups: hydrocarbyl, substituted hydrocarbyl, alkyl, alkoxy, acyl,acyloxy, alkenyl, alkenoxy, aryl, aryloxy, amino, amido, acetal,carbamyl, carbocyclo, cyano, ester, ether, halogen, heterocyclo,hydroxy, keto, ketal, phospho, nitro, and thio.

The terms “halogen” or “halo” as used herein alone or as part of anothergroup refer to chlorine, bromine, fluorine, and iodine.

The term “heteroatom” refers to atoms other than carbon and hydrogen.

The term “heteroaromatic” as used herein alone or as part of anothergroup denotes optionally substituted aromatic groups having at least oneheteroatom in at least one ring, and preferably 5 or 6 atoms in eachring. The heteroaromatic group preferably has 1 or 2 oxygen atoms and/or1 to 4 nitrogen atoms in the ring, and is bonded to the remainder of themolecule through a carbon. Exemplary groups include furyl, benzofuryl,oxazolyl, isoxazolyl, oxadiazolyl, benzoxazolyl, benzoxadiazolyl,pyrrolyl, pyrazolyl, imidazolyl, triazolyl, tetrazolyl, pyridyl,pyrimidyl, pyrazinyl, pyridazinyl, indolyl, isoindolyl, indolizinyl,benzimidazolyl, indazolyl, benzotriazolyl, tetrazolopyridazinyl,carbazolyl, purinyl, quinolinyl, isoquinolinyl, imidazopyridyl, and thelike. Exemplary substituents include one or more of the followinggroups: hydrocarbyl, substituted hydrocarbyl, alkyl, alkoxy, acyl,acyloxy, alkenyl, alkenoxy, aryl, aryloxy, amino, amido, acetal,carbamyl, carbocyclo, cyano, ester, ether, halogen, heterocyclo,hydroxy, keto, ketal, phospho, nitro, and thio.

The terms “heterocyclo” or “heterocyclic” as used herein alone or aspart of another group denote optionally substituted, fully saturated orunsaturated, monocyclic or bicyclic, aromatic or non-aromatic groupshaving at least one heteroatom in at least one ring, and preferably 5 or6 atoms in each ring. The heterocyclo group preferably has 1 or 2 oxygenatoms and/or 1 to 4 nitrogen atoms in the ring, and is bonded to theremainder of the molecule through a carbon or heteroatom. Exemplaryheterocyclo groups include heteroaromatics as described above. Exemplarysubstituents include one or more of the following groups: hydrocarbyl,substituted hydrocarbyl, alkyl, alkoxy, acyl, acyloxy, alkenyl,alkenoxy, aryl, aryloxy, amino, amido, acetal, carbamyl, carbocyclo,cyano, ester, ether, halogen, heterocyclo, hydroxy, keto, ketal,phospho, nitro, and thio.

The terms “hydrocarbon” and “hydrocarbyl” as used herein describeorganic compounds or radicals consisting exclusively of the elementscarbon and hydrogen. These moieties include alkyl, alkenyl, alkynyl, andaryl moieties. These moieties also include alkyl, alkenyl, alkynyl, andaryl moieties substituted with other aliphatic or cyclic hydrocarbongroups, such as alkaryl, alkenaryl and alkynaryl. Unless otherwiseindicated, these moieties preferably comprise 1 to 20 carbon atoms.

The term “oxygen-protecting group” as used herein denotes a groupcapable of protecting an oxygen atom (and hence, forming a protectedhydroxyl group), wherein the protecting group may be removed, subsequentto the reaction for which protection is employed, without disturbing theremainder of the molecule. Exemplary oxygen protecting groups includeethers (e.g., allyl, triphenylmethyl (trityl or Tr), p-methoxybenzyl(PMB), p-methoxyphenyl (PMP)); acetals (e.g., methoxymethyl (MOM),β-methoxyethoxymethyl (MEM), tetrahydropyranyl (THP), ethoxy ethyl (EE),methylthiomethyl (MTM), 2-methoxy-2-propyl (MOP),2-trimethylsilylethoxymethyl (SEM)); esters (e.g., benzoate (Bz), allylcarbonate, 2,2,2-trichloroethyl carbonate (Troc), 2-trimethylsilylethylcarbonate); silyl ethers (e.g., trimethylsilyl (TMS), triethylsilyl(TES), triisopropylsilyl (TIPS), triphenylsilyl (TPS),t-butyldimethylsilyl (TBDMS), t-butyldiphenylsilyl (TBDPS)) and thelike. A variety of oxygen protecting groups and the synthesis thereofmay be found in “Protective Groups in Organic Synthesis” by T.W. Greeneand P.G.M. Wuts, 3^(rd) ed., John Wiley & Sons, 1999.

The “substituted hydrocarbyl” moieties described herein are hydrocarbylmoieties which are substituted with at least one atom other than carbon,including moieties in which a carbon chain atom is substituted with aheteroatom such as nitrogen, oxygen, silicon, phosphorous, boron, or ahalogen atom, and moieties in which the carbon chain comprisesadditional substituents. These substituents include alkyl, alkoxy, acyl,acyloxy, alkenyl, alkenoxy, aryl, aryloxy, amino, amido, acetal,carbamyl, carbocyclo, cyano, ester, ether, halogen, heterocyclo,hydroxy, keto, ketal, phospho, nitro, and thio.

When introducing elements of the present invention or the preferredembodiments(s) thereof, the articles “a”, “an”, “the” and “said” areintended to mean that there are one or more of the elements. The terms“comprising”, “including” and “having” are intended to be inclusive andmean that there may be additional elements other than the listedelements.

Having described the invention in detail, it will be apparent thatmodifications and variations are possible without departing from thescope of the invention defined in the appended claims.

EXAMPLES

The following examples are included to demonstrate certain embodimentsof the invention. It should be appreciated by those of skill in the artthat the techniques disclosed in the examples represent techniquesdiscovered by the inventors to function well in the practice of theinvention. Those of skill in the art should, however, in light of thepresent disclosure, appreciate that many changes can be made in thespecific embodiments that are disclosed and still obtain a like orsimilar result without departing from the spirit and scope of theinvention, therefore all matter set forth is to be interpreted asillustrative and not in a limiting sense.

Example 1 JVM 1

To a stirred solution of MMB (50 mg, 0.189 mmol) in dichloromethane, wasadded carbonyldiimidazole (46.02 mg, 0.284 mmol). The reaction mixturewas stirred at ambient temperature for 24 hours. After completion of thereaction, the reaction mixture was diluted with chloroform (2 mL). Theorganic layer was washed with 10% citric acid solution (2 mL), driedover Na₂SO₄, and concentrated under reduced pressure. The residue waspurified by column chromatography (silica gel eluted with 3% methanol indichloromethane) to afford compound JVM 1 as an off-white solid (yield:75%).

¹H-NMR (CDCl₃, 400 MHz) δ 8.13 (s, 1H), 7.68 (s, 1H), 7.42 (s, 1H),7.09-7.05 (m, 3H), 5.72 (t, J=8 Hz, 1H), 4.94 (d, J=12 Hz, 1H), 4.55 (d,J=12.8 Hz, 2H), 4.36 (d, J=16 Hz, 1H), 3.902-3.856 (m, 1H), 2.79 (t,J=11.8 Hz, 1H), 2.60 (d, J=8 Hz, M), 2.44-1.91 (m, 8H), 1.83-1.74 (m,1H), 1.66 (t, J=12 Hz, 1H), 1.52 (s, 1H), 1.07 (t, J=12 Hz, 1H); ¹³C NMR(CDCl₃, 100 MHz) δ 174.5, 148.7, 137.7, 137.0, 133.3, 132.7, 130.9,130.6, 119.4, 117.1, 80.8, 69.8, 62.4, 59.9, 48.3, 43.7, 40.9, 36.2,26.5, 23.8, 23.6, 17.8 ppm.

Example 2 JVM 57 (6d in Example 19)

4-(2-Aminoethyl)morpholine (25 mg, 0.19 mmol) in dichloromethane (2 mL)was added at 0° C. to the triazole intermediate of MMB (JVM 2-16) (70mg, 0.19 mmol). The reaction mixture was stirred for 15 hours. Uponcompletion of the reaction, as determined by TLC, water was added to thereaction mixture and the resulting aqueous mixture was extracted withdichloromethane. The organic layer was washed with water followed bybrine, dried over anhydrous Na₂SO₄, and concentrated to afford the crudeproduct. The crude product was purified by column chromatography (silicagel eluted with 3% methanol in dichloromethane) to afford compound JVM57 as a white solid (yield: 60%).

¹H NMR (CDCl₃, 400 MHz): δ 6.11 (d, J=3.6 Hz, 1H), 5.58 (t, J=8 Hz, 1H),5.43 (d, J=2.8 Hz, 1H), 5.06 (s, 1H), 4.53 (d, J=12.4 Hz, 1H), 4.34 (d,J=12 Hz, 1H), 3.74 (t, J=8.8 Hz, 1H), 3.56 (s, 4H), 3.16 (t, J=5.2 Hz,2H), 2.78-2.72 (m, 2H), 2.32 (s, 8H), 2.21-2.00 (m, 4H), 1.55 (t, J=10.4Hz, 1H), 1.41 (s, 3H), 1.01 (t, J=12 Hz, 1H) ppm. ¹³C NMR (CDCl3, 100MHz) δ 169.2, 155.9, 138.7, 135.4, 130.2, 120.0, 80.9, 67.0, 66.7, 63.1,59.8, 57.2, 53.1, 42.5, 37.0, 36.5, 25.7, 24.4, 23.7, 17.8 ppm.

Example 3 JVM 59 (6b in Example 19)

To the triazole intermediate of MMB (JVM 2-16) (70 mg, 0.19 mmol) indichloromethane (2 mL) at 0° C. was added 1-(2-aminoethyl)pyrrolidine(21.6 mg, 0.19 mmol). The reaction mixture was stirred for 16 hours.Upon completion of the reaction, as determined by TLC, water was addedto the reaction mixture and the aqueous mixture was extracted withdichloromethane. The organic layer was washed with water followed bybrine, dried over anhydrous Na₂SO₄, and concentrated to afford the crudeproduct. The crude product was purified by column chromatography (silicagel eluted with 5% methanol in dichloromethane) to afford compound JVM59 as a white solid (yield: 55%).

¹H NMR (CDCl₃, 400 MHz): δ 6.22 (d, J=3.2 Hz, 1H), 5.65 (t, J=7 Hz, 1H),5.55 (s, 1H), 4.62 (d, J=11.6 Hz, 1H), 4.47 (d, J=12.4 Hz, 1H), 3.82 (t,J=9.6 Hz, 1H), 3.35 (s, 2H), 2.90-2.83 (m, 2H), 2.70 (s, 4H), 2.42 (d,J=9.6 Hz, 2H), 2.38-2.13 (m, 7H) 1.84 (s, 4H), 1.66 (t, J=12 Hz, 1H),1.52 (s, 3H), 1.13 (t, J=11.6 Hz, 1H) ppm. ¹³C NMR (CDCl3, 100 MHz) δ169.3, 156.1, 138.6, 135.3, 129.8, 120.1, 80.9, 67.0, 63.1, 59.8, 55.1,53.8, 42.5, 38.9, 36.5, 25.6, 24.3, 23.6, 23.2, 17.8 ppm.

Example 4 JVM 61 (6c in Example 19)

To the triazole intermediate of MMB (JVM 2-16) (70 mg, 0.19 mmol) indichloromethane (2 mL), 2-ethylaminopyridine (23.18 mg, 0.19 mmol) wasadded at 0° C. The reaction mixture was stirred for 16 hours. Uponcompletion as determined by TLC, water was added to the reaction mixtureand the aqueous mixture was extracted with dichloromethane. The organiclayer was washed with water followed by brine, dried over anhydrousNa₂SO₄, and concentrated to afford the crude product. The crude productwas purified by column chromatography (silica gel eluted with 5%methanol in dichloromethane) to afford compound JVM 61 as a white solid(yield: 65%).

¹H NMR (CDCl₃, 400 MHz): δ 8.50 (s, 1H), 7.62 (t, J=7.2 Hz, 1H), 7.15(d, J=7.6 Hz, 2H), 6.19 (s, 1H), 5.64 (t, J=8 Hz, 1H), 5.56 (m, 2H),4.62 (d, J=12.4 Hz, 1H), 4.44 (d, J=12.8 Hz, 1H), 3.84 (t, J=9.2 Hz,1H), 3.60 (d, J=6 Hz, 2H), 2.99-2.82 (m, 4H), 2.41-2.12 (m, 5H), 1.75(s, 1H), 1.64 (d, J=10.4 Hz, 1H), 1.52 (s, 3H), 1.07 (t, J=13.6 Hz, 1H).¹³C NMR (CDCl₃, 100 MHz): δ 169.3, 159.1, 156.0, 149.1, 138.6, 136.6,135.5, 129.9, 123.4, 121.6, 120.2, 81.0, 67.0, 63.2, 59.8, 42.5, 40.1,37.1, 36.6, 25.8, 24.4, 23.7, 17.9 ppm.

Example 5 JVM 64 (6e in Example 19)

To the triazole intermediate of MMB (JVM 2-16) (70 mg, 0.19 mmol) indichloromethane (2 mL), 5-(methylthio)-1H-1,2,4-triazol-3-amine (24.7mg, 0.19 mmol) was added at 0° C. The reaction mixture was stirred for 8hours. Upon completion as determined by TLC, water was added to thereaction mixture and the aqueous mixture was extracted withdichloromethane. The organic layer was washed with water followed bybrine, dried over anhydrous Na₂SO₄, and concentrated to afford the crudeproduct. The crude product was purified by column chromatography (silicagel eluted with 3% methanol in dichloromethane) to afford compound JVM64 as a white solid (yield: 62%).

¹H NMR (CDCl₃, 400 MHz): δ 6.22 (s, 2H), 5.82 (t, J=8 Hz, 1H), 5.50 (s,1H), 4.90 (d, J=12.4 Hz, 1H), 4.81 (d, J=12.4 Hz, 1H), 3.85 (t, 9.6 Hz,1H), 2.95 (s, 1H), 2.85 (d, J=9.2 Hz, 1H), 2.48-2.15 (m, 8H), 1.70-1.53(m, 6H), 1.13 (t, J=12.4 Hz, 1H); ¹³C NMR (CDCl₃, 100 MHz): δ 169.1,163.1, 157.4, 149.9, 138.5, 133.3, 132.7, 120.2, 80.7, 70.1, 62.9, 59.7,42.4, 36.2, 25.6, 24.3, 23.7, 17.8, 13.5 ppm.

Example 6 JVM 66

To a stirred solution of MMB (50 mg, 0.19 mmol) in chloroform (2 mL),thiocarbonyldiimidazole (33.8 mg, 0.19 mmol) was added at ambienttemperature. The reaction was maintained for 1 hour at ambienttemperature. Upon completion as determined by TLC, water was added andthe aqueous mixture was extracted with dichloromethane. The organiclayer was dried over anhydrous Na₂SO₄ and concentrated to afford thecrude product. The crude product was purified by column chromatography(silica gel eluted with a gradient of 3-8% methanol in dichloromethane)to afford compound JVM 66 as an off-white solid (yield: 60%) andcompound JVM 66A as a white solid (yield: 15%).

¹H NMR (CDCl₃, 400 MHz): δ 8.11 (s, 1H), 7.38 (s, 1H), 7.07 (s, 1H),6.22 (s, 1H), 5.52 (s, 2H), 5.14 (s, 1H), 4.30 (s, 1H), 3.78 (t, J=8.8Hz, 1H), 3.16 (s, 1H), 2.94 (d, J=8.8 Hz, 1H), 2.47 (q, J=17.2 Hz, 2H),2.3-2.18 (m, 3H), 1.77-1.66 (m, 2H), 1.39 (s, 3H), 1.32-1.23 (m, 1H);¹³C NMR (CDCl₃, 100 MHz): δ 168.9, 165.1, 143.8, 138.7, 135.2, 131.0,119.8, 116.4, 115.6, 79.4, 63.0, 59.8, 53.3, 45.1, 37.4, 29.8, 28.2,24.7, 17.8 ppm.

Example 7 JVM 67

To a reaction mixture of MMB (200 mg, 0.76 mmol) and triethylamine (76.7mg, 0.76 mmol) in dichloromethane (5 mL), succinic anhydride (76 mg,0.76 mmol) was added at ambient temperature. The resulting reactionmixture was stirred for 48 hours. Upon completion as determined by TLC,the reaction mixture was concentrated under reduced pressure to affordthe crude product. The crude product was purified by columnchromatography (silica gel eluted with a gradient of 3-5% methanol indichloromethane) to afford compound JVM 67 as a white solid (yield:90%).

¹H NMR (DMSO-d₆, 400 MHz): δ 12.25 (s, 1H), 6.05 (d, J=2.8 Hz, 1H),5.64-5.57 (m, 2H), 4.64 (d, J=12.4 Hz, 1H), 4.42 (d, J=12.8 Hz, 1H),4.12 (t, J=9.6 Hz, 1H), 2.99 (t, J=3 Hz, 1H), 2.85 (d, J=9.6 Hz, 1H),2.30-2.04 (m, 10H), 1.66 (t, J=11.6 Hz, 1H), 1.47 (s, 3H), 0.96 (t,J=11.6 Hz, 1H); ¹³C NMR (DMSO-d₆, 100 MHz): δ 173.8, 172.4, 169.8,140.0, 135.3, 129.5, 119.7, 110.0, 81.0, 66.9, 63.0, 60.3, 42.2, 36.7,29.1, 25.0, 24.2, 23.6, 17.9 ppm.

Example 8 JVM 88

To a stirred solution of MMB (50 mg, 0.19 mmol) in dichloromethane (2mL), was added 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide (EDC, 43.93mg, 0.23 mmol), triethylamine (48.4 mg, 0.48 mmol),dimethylaminopyridine (DMAP, 2.3 mg, 0.019 mmol) and1-piperidylpropionic acid (29.8 mg, 0.19 mmol) at 0° C. The reactionmixture was stirred at ambient temperature for 24 hours. Uponcompletion, water was added and the mixture was extracted withdichloromethane. The organic layer was washed with water followed bybrine, dried over anhydrous Na₂SO₄, and concentrated to afford the crudeproduct. The crude product was purified by column chromatography (silicagel eluted with 2% methanol in dichloromethane) to afford compound JVM88 as a white solid (yield: 62%).

¹H NMR (CDCl₃, 400 MHz): δ 6.23 (d, J=3.6 Hz, 1H), 5.65 (t, J=8 Hz, 1H),5.52 (d, J=3.2 Hz, 1H), 4.69 (d, J=12.4 Hz, 1H), 4.42 (d, J=12.4 Hz,1H), 3.84 (t, J=9.2 Hz, 1H), 2.85-2.81 (m, 2H), 2.65-2.62 (m, 2H),2.52-2.48 (m, 2H), 2.42-2.12 (m, 10H), 1.63-1.52 (m, 8H), 1.41 (d, J=4.4Hz, 2H), 1.10 (t, J=12 Hz, 1H); ¹³C NMR (CDCl₃, 100 MHz): δ 172.4,169.4, 138.8, 135.0, 130.5, 120.4, 81.1, 66.6, 63.4, 60.0, 54.4, 54.3,42.7, 36.7, 32.3, 25.9, 25.8, 24.4, 24.2, 23.9, 18.1 ppm.

Example 9 JVM 96

To a reaction mixture of MMB carboxylic acid (JVM 67), (50 mg, 0.14mmol), EDC (40.26 mg, 0.21 mmol), N-hydroxybenzotriazole (HOBt, 28.35mg, 0.21 mmol), and triethylamine (42.42 mg, 0.42 mmol) indichloromethane (2 mL) was added 3-aminomethyl-6-chloropyridine (19.96mg, 0.14 mmol) at 0° C. and the reaction mixture was stirred at ambienttemperature for 16 hours. Upon completion as determined by TLC, waterwas added and the mixture extracted with dichloromethane. The organiclayer was dried and concentrated to afford the crude compound. The crudeproduct was further purified by column chromatography (silica gel using3% methanol in dichloromethane) to afford JVM 96 as pure product aswhite solid (yield 75%).

¹H NMR (CDCl₃, 400 MHz): δ 8.28 (s, 1H), 7.61 (d, J=8.4 Hz, 1H), 7.29(d, J=8.4 Hz, 1H), 6.22 (d, J=3.2 Hz, 1H), 6.07 (s, 1H), 5.68 (t, J=7.2Hz, 1H), 5.55 (s, 1H), 4.65 (d, J=12.4 Hz, 1H), 4.49 (d, J=12.8 Hz, 1H),4.42 (d, J=5.6 Hz, 2H), 3.85 (t, J=9.6 Hz, 1H), 2.95 (t, J=8.8 Hz, 1H),2.85 (d, J=9.6 Hz, 1H), 2.68 (t, J=6 Hz, 2H), 2.52-2.11 (m, 7H),1.67-1.62 (m, 2H), 1.53 (s, 3H), 1.12 (t, J=11.6 Hz, 1H); ¹³C NMR(CDCl₃, 100 MHz): δ 172.8, 171.5, 169.6, 150.7, 148.9, 138.9, 138.6,134.8, 133.1, 130.8, 124.4, 120.4, 81.2, 67.2, 63.3, 60.1, 42.7, 40.5,36.7, 30.7, 29.3, 25.8, 24.6, 23.9, 18.1 ppm.

Example 10 JVM 2-16

To a stirred solution of MMB (50 mg, 0.18 mmol) in dichloromethane,carbonylditriazole (46.5 mg, 0.28 mmol) was added at ambienttemperature. The reaction mixture was stirred at ambient temperature for10 minutes. Upon completion, water was added and the mixture extractedwith dichloromethane, dried over Na₂SO₄ and concentrated under reducedpressure to afford pure product JVM 2-16 as white solid (yield: 85%).

¹H NMR (CDCl₃, 400 MHz): δ 8.83 (s, 1H), 8.06 (s, 1H), 6.26 (d, J=3.6Hz, 1H), 5.92 (t, J=8.4 Hz, 1H), 5.55 (d, J=3.2 Hz, 1H), 5.08 (d, J=11.6Hz, 1H), 4.90 (d, J=12 Hz, 1H), 3.89 (t, J=9.6 Hz, 1H), 2.91 (m, 2H),2.56-2.17 (m, 6H), 1.84-1.72 (m, 1H), 1.55 (s, 3H), 1.17 (t, J=12.4 Hz,1H); ¹³C NMR (CDCl₃, 100 MHz): δ 169.2, 154.0, 147.7, 145.8, 138.6,134.4, 133.3, 120.6, 80.9, 71.5, 63.3, 59.9, 42.7, 36.5, 25.7, 24.3,24.1, 18.1 ppm.

Example 11 JVM 2-26

To a stirred solution of MMB (50 mg, 0.18 mmol) in dichloromethane (2mL), carbonylditriazole (46.5 mg, 0.28 mmol) was added at ambienttemperature. The reaction mixture was stirred for 10 minutes andpiperidine-1-propanol (40 mg, 0.28 mmol) was added, and the reactionmixture was maintained at ambient temperature for 30 minutes. Uponcompleted as determined by TLC, water was added and the mixtureextracted with dichloromethane. The organic layer was dried over Na₂SO₄and concentrated to afford a crude product. The crude compound waspurified by column chromatography (silica gel eluted with 3% methanol indichloromethane) to afford pure product JVM 2-26, as a white solid(yield: 81%).

¹H NMR (CDCl₃, 400 MHz): δ 6.24 (d, J=3.6 Hz, 1H), 5.74 (t, J=7.6 Hz,1H), 5.55 (d, J=3.2 Hz, 1H), 4.65 (d, J=12 Hz, 1H), 4.55 (d, J=12 Hz,1H), 4.19 (t, J=6 Hz, 2H), 3.86 (t, J=8.8 Hz, 1H), 2.88-2.82 (m, 2H),2.46-2.13 (m, 12H), 1.92 (s, 2H), 1.70-1.64 (m, 5H), 1.53 (s, 3H), 1.45(s, 2H), 1.13 (t, J=11.6 Hz, 1H); ¹³C NMR (CDCl₃, 100 MHz): δ 169.5,155.0, 138.7, 134.5, 131.7, 120.4, 81.1, 70.3, 66.8, 63.4, 60.0, 55.5,54.5, 42.7, 36.6, 25.9, 25.5, 24.5, 24.1, 24.1, 23.9, 18.1 ppm.

Example 12 JVM 2-31

To a stirred solution of MMB (50 mg, 0.18 mmol) in dichloromethane atambient temperature, was added carbonylditriazole (46.5 mg, 0.28 mmol).The reaction mixture was stirred for 10 minutes. 6-Amino-1-hexanol (32.7mg, 0.28 mmol) was then added and the reaction was maintained for 30minutes at ambient temperature. Upon completion of the reaction, asdetermined by TLC, water was added and the mixture extracted withdichloromethane. The organic layer was dried over anhydrous Na₂SO₄ andconcentrated to afford the crude product. The crude compound waspurified by column chromatography (silica gel eluted with 3% methanol indichloromethane) to afford the pure product, JVM 2-31, as a colorlessoil (yield: 85%).

¹H NMR (CDCl₃, 400 MHz): δ 6.28 (d, J=3.6 Hz, 1H), 5.73 (t, J=8 Hz, 1H),5.59 (d, J=3.2 Hz, 1H), 4.68-4.63 (m, 2H), 4.51 (d, J=12.4 Hz, 1H), 3.90(t, J=9.2 Hz, 2H), 3.68 (t, J=6 Hz, 2H), 3.21 (d, J=6.4 Hz, 2H),2.98-2.88 (m, 2H), 2.46-2.16 (m, 6H), 1.71-1.51 (m, 8H), 1.45-1.36 (m,4H), 1.16 (t, d, J=11.6 Hz, 1H) ppm; ¹³C NMR (CDCl₃, 100 MHz): δ 169.6,156.3, 138.9, 135.7, 130.3, 120.3, 81.2, 67.2, 63.4, 62.8, 60.1, 42.7,41.0, 36.7, 32.6, 30.0, 26.5, 25.9, 25.4, 24.7, 23.9, 18.1 ppm.

Example 13 JVM 2-35

To a stirred solution of MMB (50 mg, 0.18 mmol) in dichloromethane,carbonylditriazole (46.5 mg, 0.28 mmol) was added at ambienttemperature. The reaction mixture was stirred for 10 minutes.N,N-dimethylethanolamine (24.9 mg, 0.28 mmol) was then added and thereaction was maintained for 30 minutes at ambient temperature. Uponcompletion as determined by TLC, water was added and the mixtureextracted with dichloromethane. The organic layer was dried over Na₂SO₄and concentrated to afford the crude product. The crude compound waspurified by column chromatography (silica gel eluted with 4% methanol indichloromethane) to afford the pure product, JVM 2-35 as a white solid(yield: 81%).

¹H NMR (CDCl₃, 400 MHz) δ 6.24 (d, J=3.6 Hz, 1H), 5.74 (t, J=8.4 Hz,1H), 5.55 (d, J=3.2 Hz, 1H), 4.65 (d, J=12 Hz, 1H), 4.56 (d, J=12.4 Hz,1H), 4.24 (s, 2H), 3.85 (t, J=9.6 Hz, 1H), 2.84 (d, J=9.2 Hz, 2H), 2.62(s, 2H), 2.47-2.12 (m, 12H), 1.72-1.60 (m, 1H), 1.53 (s, 3H), 1.12 (t,J=11.6 Hz, 1H); ¹³C NMR (CDCl₃, 100 MHz): δ 169.5, 155.1, 138.7, 134.5,131.6, 120.5, 81.1, 70.4, 65.4, 63.4, 60.0, 57.6, 45.6, 42.7, 36.6,25.8, 24.4, 23.9, 18.1 ppm.

Example 14 JVM 2-40

To a stirred solution of MMB (50 mg, 0.18 mmol) in methanol (2 mL),carbonylditriazole (46.5 mg, 0.28 mmol) was added at ambienttemperature. The reaction mixture was stirred at same temperature for 1hour. Upon completion as determined by TLC, the reaction mixture wasconcentrated under reduced pressure and the crude compound was purifiedby column chromatography (silica gel eluted with 2% methanol indichloromethane) to afford pure product, JVM 2-40, as a white solid(yield: 80%).

¹H NMR (CDCl₃, 400 MHz): δ 6.24 (s, 1H), 5.72 (s, 1H), 5.53 (s, 1H),4.65 (d, t, J=11.6 Hz, 1H), 4.56 (d, J=12 Hz, 1H), 3.85 (t, J=9.6 Hz,1H), 3.77 (s, 3H), 2.83 (d, J=9.6 Hz, 2H), 2.44-2.13 (m, 6H), 1.66 (t,J=11.6 Hz, 1H), 1.52 (s, 3H), 1.12 (t, J=11.6 Hz, 1H); ¹³C NMR (CDCl₃,100 MHz): δ 169.4, 155.7, 138.7, 134.5, 131.6, 120.4, 81.1, 70.4, 63.4,60.0, 55.1, 42.7, 36.6, 25.8, 24.4, 23.9, 18.1 ppm.

Example 15 JVM 2-41

To a stirred solution of MMB (50 mg, 0.18 mmol) in dichloromethane, wasadded carbonylditriazole (46.5 mg, 0.28 mmol). The reaction mixture wasstirred at room temperature for 10 minutes, and mercaptoethanol (21.84mg, 0.28 mmol) was added. The reaction was maintained for 30 minutes.Upon completion as determined by TLC, water was added and the mixtureextracted with dichloromethane. The organic layer was dried over Na₂SO₄and concentrated to afford the crude product. The crude compound waspurified by column chromatography (silica gel eluted with 4% methanol indichloromethane) to afford the pure product, JVM 2-41, as an oil (yield:65%).

¹H NMR (CDCl₃, 400 MHz): δ 5.11 (t, J=8 Hz, 1H), 5.02 (d, J=12 Hz, 1H),4.62 (d, J=12 Hz, 1H), 3.90-3.76 (m, 4H), 3.07-3.02 (m, 3H), 2.84-2.74(m, 3H), 2.61-2.57 (m, 1H), 2.47-2.12 (m, 7H), 1.99 (s, 4H), 1.63-1.57(m, 1H), 1.53 (s, 3H), 1.11 (t, J=12.4 Hz, 1H); ¹³C NMR (CDCl₃, 100MHz): δ 175.9, 171.6, 134.7, 131.3, 81.2, 70.0, 63.3, 61.8, 60.9, 60.0,46.8, 42.7, 36.8, 36.6, 34.0, 29.7, 26.7, 24.2, 23.8, 18.0 ppm.

Example 16 JVM 2-49

To the stirred solution of MMB (70 mg, 0.27 mmol) in dichloromethane,dimethylamine (14.40 mg, 0.32 mmol) in methanol was added the reactionmixture was maintained under ambient conditions for 2 hours. Uponcompletion, the reaction mixture was concentrated to remove solvent. Thecrude reaction mixture dissolved in dichloromethane and added thethiocarbonyldiimidazole (72 mg, 0.41 mmol). The reaction mixture wasmaintained at ambient temperature for 3 hours. Upon completion, thereaction mixture was concentrated and purified by column chromatography(silica gel eluted with 3% methanol in dichloromethane) to afford pureproduct.

¹H NMR (CDCl₃, 400 MHz): δ 8.12 (s, 1H), 7.38 (s, 1H), 7.07 (s, 1H),5.51 (s, 1H), 5.19 (s, 1H), 4.32 (t, J=8 Hz, 1H), 3.80 (t, J=8 Hz, 1H),2.99-2.03 (m, 17H), 1.6 (s, 1H), 1.41 (s, 3H), 1.29-1.23 (m, 1H); ¹³CNMR (CDCl₃, 100 MHz): δ 176.5, 165.4, 144.2, 135.5, 131.1, 116.8, 115.9,79.7, 63.4, 60.0, 57.8, 53.8, 45.8, 45.3, 37.8, 30.0, 28.3, 26.1, 21.1,18.0 ppm.

Example 17 Antileukemic Activity of Various MMB Derivatives

Derivatives were screened for antileukemic activity against AML cells inculture (See FIGS. 1-7). Compounds JVM 64, JVM 66, JVM 2-26, and JVM2-49 (Examples 5, 6, 11, and 16, respectively) were the most activecompounds against AML 052308 cells in culture and were more potent thanMMB. JVM 66 (a thiocarbamate derivative of MMB, Example 6) was the mostactive molecule of this group with an LC₅₀ value of 2.6 μM, and wasabout 6-fold more cytotoxic than MMB (LC₅₀=16 μM); JVM 66 was also3-fold more potent than parthenolide (LC₅₀=7.6 μM). The derivatives JVM2-26, JVM 2-49, and JVM 64 (Examples 11, 16, and 5, respectively)exhibited similar cytotoxicity to parthenolide (LC₅₀=5, 5.2, 7.4 μM) andwere 3-fold more cytotoxic than MMB against AML 052308 cells. JVM 61(Example 4), JVM 59 (Example 3), and JVM 74 showed almost equalcytotoxicity to MMB, while JVM 57 (Example 2) and JVM 58 were lessactive than MMB. Compound JVM 88 (Example 8) was screened forantileukemic activity against the M9 ENL cell line, and against the AML123009 and AML 100510 primary isolates, exhibiting good antileukemicactivity compared to MMB in these cellular assays.

Carbamate and carbonate derivatives of MMB were also screened foractivity against M9 ENL cells at concentrations of 5, 10 and 20 μM (FIG.10). JVM 2-66, JVM 2-60, JVM 2-59, and JVM 2-49 reduced cell viabilityby greater than 50% at the lowest concentration tested. Additionally,succinic amide derivatives of MMB were screened for activity against M9ENL cells at concentrations of 5, 10 and 20 μM (FIG. 11). JVM 2-70reduced cell viability by greater than 50% at the lowest concentrationtested.

Example 18 In Vitro Growth Inhibition and Cytotoxicity

The compounds disclosed herein were also screened for anticanceractivity against a panel of 60 human tumor cell lines. The compoundswere first screened at a single concentration of 10⁻⁵ M. Compounds whichshowed more than 60% growth inhibition in at least eight human cancercell lines from the panel were selected for a complete dose-responsestudy at five concentrations: 10⁻⁴ M, 10⁻⁵ M, 10⁻⁶ M, 10⁻⁷ M, and 10⁻⁸M. From the initial single dose screening, 16 compounds were selectedfor a five-dose screening: JVM 2-13 (Table 3), JVM 2-26 (Table 4), JVM2-31 (Table 5), JVM 2-35 (Table 6), JVM 2-40 (Table 7), JVM 2-44 (Table8), JVM 2-50 (Table 9), JVM 2-57 (Table 10), JVM 2-66 (Table 11), JVM2-70 (Table 12), JVM-57 (6d) (Table 13), JVM-59 (6b) (Table 14), JVM-61(6c) (Table 15), JVM-64 (6e) (Table 16), JVM-66 (Table 17), and JVM-96(Table 18).

Example 19 Anti-Cancer Activity of Carbamate Derivatives ofMelampomagnolide B (MMB)

Parthenolide (PTL; 1, FIG. 8), a sesquiterpene lactone isolated from themedicinal herb Feverfew (Tanacetum parthenium), has been widely reportedin the literature as an anticancer agent that is effective against bothhematological and solid tumors.^(1,2) PTL and its analogs promoteapoptosis by inhibiting the activity of the NF-κB transcription factorcomplex, and thereby down-regulates anti-apoptotic genes under NF-κBcontrol.³ Recent studies also demonstrate that PTL induces robustapoptosis of primary acute myeloid leukemia (AML) stem cells inculture.^(4,5) AML is a clonal malignancy of the hematopoietic systemcharacterized by accumulation of immature cell populations in the bonemarrow or peripheral blood,⁶ and is the most common type of leukemia inadults but has the lowest survival rate of all leukemias.⁷

More recently, we have shown that PTL and PTL analogs also selectivelyinduce almost complete glutathione depletion and severe cell death inCD34+ AML cells,⁸ but exhibit significantly less toxicity in normalCD34+ cells. PTL analogs perturb glutathione homeostasis by amultifactorial mechanism, including inhibition of key glutathionemetabolic enzymes (GCLC and GPX1), and direct depletion of glutathione.Thus, primitive leukemia cells are uniquely sensitive to agents thattarget aberrant glutathione metabolism, an intrinsic property of primaryhuman AML cells.

PTL is a major source for several novel anti-leukemic compounds arisingfrom our research program over the past decade. The two best examplesare dimethylaminoparthenolide (DMAPT; 2, FIG. 8) and melampomagnolide B(MMB; 3, FIG. 8). MMB is a melampolide originally isolated from Magnoliagrandiflora. ⁹ MMB can be synthesized from commercially available PTLvia SeO₂/tBuOOH oxidation.^(10,11) Both of the above compounds 2 and 3have been identified as new antileukemic sesquiterpenes with propertiessimilar to PTL.^(11,12) DMAPT is currently in Phase 1 clinical studiesfor evaluation as a treatment for acute myeloid leukemia cell (AML).¹²

More importantly, from a drug design point of view, MMB is a moreintriguing molecule than either PTL or DMAPT because of the presence ofthe primary hydroxyl group at C-14, which can be structurally modifiedto improve potency, water solubility, bio-availability and tissuetargeting of the molecule.

In the current study, we have prepared a series of novel carbamateanalogs of MMB. These compounds were initially designed as potentialprodrugs of MMB. However, we have found that on examining the anticanceractivity of these compounds, several of the molecules exhibitedsignificant growth inhibition properties in a panel of sixty humancancer cell lines. Two of these compounds exhibited GI₅₀ values of ≦10μM against the majority of the human cancer cell lines in the panel.

Carbamate analogs of MMB were prepared by reaction of thep-nitrophenyloxycarbonyl ester of MMB¹³ with a variety of primary andsecondary heterocyclic amines containing pyrrolidine, morpholine,piperidine, imidazole, triazole and pyridine moieties, to affordcarbamate products 6a-6g¹⁴ with generally improved water-solubility(Scheme 4, Table 1) compared to MMB. The key p-nitrophenyloxycarbonylester of MMB was prepared by the reaction of MMB withp-nitrophenylchloroformate in the presence of triethylamine. Allconjugation reactions were carried out at ambient temperature indichloromethane. We have reported previously that the reaction ofsesquiterpenes containing an exocyclic double bond attached to the13-position of the 5-membered lactone ring with primary and secondaryamines leads to the facile formation of Michael addition products.¹⁵However, under the reaction conditions employed in Scheme 4, the rate ofO-carbamoylation appears to be much faster than the rate of C-13 Michaeladdition, and only in a few cases, with amines such as2-morpholinoethylamine, 2-piperidinoethylamine and3-aminopropylimidazole, were Michael addition byproducts observed(usually in low yields of 5-10%), due likely to the high nucleophilicityof these amines.

All compounds were purified by column chromatography (silica gel;methanol/dichloromethane) to afford pure compounds in 50-75% yield. Thesynthesized compounds were fully characterized by ¹H NMR, ¹³C NMR andhigh resolution mass spectral analysis.¹⁴

TABLE 1 Structures, reaction conditions, yields, and melting points forcarbamate analogs of melampomagnolide B Amine Product Yield (%) Time (h)Mp (° C.)

  6a 50 12 150

67 12  50

  6c 72  8 150

  6d 65  6  80

  6e 70  8 107

  6f 75  5  70

  6g 68  8  60

The above carbamate analogs were evaluated for growth inhibitionproperties against a panel of 60 human cancer cell lines derived fromnine human cancer cell types, grouped into disease sub-panels thatrepresent leukemia, lung, colon, central nervous system (CNS), melanoma,renal, ovary, breast, and prostate cancer cells. Growth inhibitory(GI₅₀) effects were measured as a function of the variation of opticaldensity as a percentage of control.^(16,17) Initial screening assayswere carried out at a single concentration of 10 μM. Five analogs,6a-6e, were identified as hits based on their ability to inhibit by 60%the growth of at least 8 of the 60 tumor cell lines in the panel. Thesefive analogs were then evaluated in 5-dose assays over the concentrationrange 10⁴-10⁸ μM, and their GI₅₀ values against the tumor cell lines inthe panel determined (Table 2). Two analogs, 6a and 6e, were identifiedas lead compounds and generally exhibited improved growth inhibitionagainst all human tumor cell lines when compared to PTL (1) and DMAPT(2), with the exception of the leukemia cell line subpanel; in thesecell lines, the GI₅₀ values for DMAPT compared very favorably with thosefor both 6a and 6e. Compound 6a exhibited potency against leukemia cellline CCRF-CEM, melanoma cell line MDA-MB-435 and breast cancer cell lineMDA-MB-468 in the nanomolar range with GI₅₀ values of 680, 460 and 570nM, respectively. Compound 6e was found to possess potent anti-leukemicactivity against leukemia cell line CCRF-CEM, non-small cell lung cancercell line HOP-92 and renal cancer cell line RXF 393 with GI₅₀ values of620, 650 and 900 nM, respectively, (Table 2).

Compounds 6a and 6e also exhibited significant growth inhibition againstthe following sub-panels of human cancer cell lines: non-small cell lungcancer (GI₅₀ values 0.65-1.45 μM); colon cancer (GI₅₀ values 1.12-2.06μM); melanoma (GI₅₀ values 0.46-2.84 μM); renal cancer _((GI50) values0.90-2.60 μM); and breast cancer (GI₅₀ values 0.57-3.07 μM) (Table 2).

We have determined the hydrolytic stability of the above five carbamatederivatives in human plasma and have shown that compounds 6b-6e havehalf-lives in the range 100-180 min, while compound 6a has a much longerhalf-life of 8 h in human plasma. Thus, we consider compounds 6b-6d tobe anticancer agents that are also metabolized by plasma esterases tothe active parent compound MMB, while compound 6a would be considered amore potent anticancer agent than MMB that is likely not metabolized toMMB in vivo.

The above results are interesting for a number of reasons: first, theantileukemic activities of 6a and 6e against the sub-panel of humanleukemia cells indicates that these carbamate analogs of MMB are morepotent than the parent compound. Second, the potent growth inhibition ofhuman solid tumor cell lines by 6a and 6e is the first report of suchactivities for MMB analogs.

Third, these interesting results indicate that structural modificationof the MMB molecule through appropriate carbamoylation of the primaryhydroxyl group can lead to an improvement in the anticancer propertiesof MMB.

The above MMB analogs, like PTL and DMAPT, are inhibitors of the NFκBpathway, activators of the nuclear kinase JNK, and selectively depleteglutathione levels in hematopoietic cancer stem cells, leading to anincrease in reactive oxygen species (ROS) and subsequent apoptosis (FIG.9).^(4,8,11) We have recently shown that hematopoietic cancer stem cellshave lower levels of reduced glutathione (GSH) and increased levels ofoxidized glutathione (GSSG) when compared to normal stem cells, and arethus more vulnerable to agents such PTL and MMB and its analogs thatinduce oxidative stress through generation of ROS.¹¹ Specifically, PTLand MMB analogs inhibit several crucial enzymes in the glutathionepathway (i.e., GCLC and GPX1) leading to severe depletion of cellularglutathione and resulting in oxidative stress and apoptosis.

In summary, we have reported on a series of novel carbamate derivativesof MMB derived from heterocyclic and heteroaromatic amines. Among thesederivatives, compounds 6a and 6e have been identified as potentanticancer agents with growth inhibition activities in the nanomolarrange against a variety of hematological and solid tumor cell lines.Analogs 6a and 6e exhibit promising anti-leukemic activity against humanleukemia cell line CCRF-CEM with GI₅₀ values of 680 and 620 nM,respectively. Compound 6a also exhibits GI₅₀ values of 460 and 570 nMagainst MDA-MB-435 melanoma and MDA-MB-468 breast cancer cell lines,respectively, and 6e has GI₅₀ values of 650 and 900 nM against HOP-92non-small cell lung and RXF 393 renal cancer cell lines, respectively.Further structure—activity relationship studies will focus on thestructural optimization of these interesting lead analogs and on themolecular basis for their mechanism of action.

TABLE 2 Growth inhibition (GI₅₀; μM)^(b) data for PTL (1), DMAPT (2) andcarbamoylated MMB analogs 6a-6e against a panel of human cancer celllines 1a^(a) 2a^(a) 6a 6b 6c 6d 6e Panel/cell line GI₅₀ GI₅₀ GI₅₀ GI₅₀GI₅₀ GI₅₀ GI₅₀ Leukemia CCRF-CEM 7.94 1.99 0.68 2.49 2.65 3.03 0.62HL-60(TB) 5.01 1.58 2.04 4.15 ND 3.59 ND K-562 19.9 2.51 3.45 3.26 ND3.37 ND MOLT-4 15.8 3.16 2.05 3.48 5.54 5.00 2.32 RPMI-8226 7.94 2.511.98 8.71 8.20 5.72 2.57 SR  ND^(c) ND 1.38 10.2 4.10 3.65 2.36Non-small cell lung cancer HOP-92 12.5 10.0 1.45 2.25 2.25 2.30 0.65NCI-H522 5.01 2.51 1.25 1.78 1.64 2.13 1.26 Colon cancer COLO 205 15.831.6 2.06 4.78 3.54 8.89 1.79 HCT-116 10.0 5.01 1.41 3.18 1.89 2.87 1.13SW-620 15.8 3.98 1.46 3.46 3.13 3.48 1.12 CNS cancer SF-539 19.9 2.511.98 15.0 5.77 14.4 1.76 SNB-75 50.1 ND 6.13 18.0 3.78 19.5 1.71Melanoma LOX IMVI 7.94 10.0 2.23 7.88 4.96 4.84 1.95 MALME-3M 12.5 ND1.90 4.18 7.52 6.12 2.32 M14 ND 15.8 2.84 9.65 5.58 7.97 1.59 MDA-MB-435ND 7.94 0.46 6.56 6.01 5.89 2.24 Ovarian cancer IGROV1 19.9 19.9 2.314.09 14.4 3.49 3.66 OVCAR-3 19.9 12.5 1.69 8.41 ND 6.20 ND Renal cancerACHN ND 15.8 1.79 3.80 2.75 3.74 1.75 CAKI-1 10.0 12.5 2.03 6.86 2.884.31 1.99 RXF 393 12.5 15.8 1.20 4.08 2.22 3.00 0.90 TK-10 ND 3.16 2.603.11 3.78 3.93 2.51 Prostate cancer DU-145 ND 5.01 2.44 7.42 4.59 3.743.49 Breast cancer MCF7 15.8 5.01 1.62 3.91 2.85 3.54 1.33 BT-549 ND5.01 2.69 4.75 2.60 4.99 1.47 T-47D ND 39.8 3.07 4.86 6.19 6.32 2.23MDA-MB-468 ND ND 0.57 2.30 3.22 3.26 1.29 GI₅₀ values <1 μM are bolded.^(a)GI₅₀ values obtained from NCI database. ^(b)GI₅₀, concentration ofanalog (μM) that halves cellular growth. ^(c)ND not determined.

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Phytochemistry 1984, 23, 2372.-   10. Macias, F. A.; Galindo, J. C. G.; Massanet, G. M. Phytochemistry    1992, 31, 1969.-   11. Shama, N.; ShanShan, P.; Fred, K. H.; Craig, T. J.; Peter, A. C.    Bioorg. Med. Chem. 2011, 19, 1515.-   12. Guzman, M. L.; Rossi, R. M.; Neelakantan, S.; Li, X.;    Corbett, C. A.; Hassane, D. C.; Becker, M. W.; Bennett, J. M.;    Sullivan, E.; Lachowicz, J. L.; Vaughan, A.; Sweeney, C. J.;    Matthews, W.; Carroll, M.; Liesveld, J. L.; Crooks, P. A.;    Jordan, C. T. Blood 2007, 110, 4427.-   13. Synthetic procedure and analytical data for the    p-nitrophenyloxycarbonyl ester of MMB (5): To the reaction mixture    of MMB (100 mg, 0.378 mmol) and triethylamine (45.8 mg, 0.454 mmol)    in dichloromethane (2 mL), p-nitrophenylchloroformate (76.3 mg,    0.378 mmol) was added at 0° C. The reaction mixture was stirred for    24 h at ambient temperature. When the reaction was completed    (monitored by TLC), water was added to the reaction mixture and the    aqueous mixture was extracted with dichloromethane. The organic    layer was washed with water, followed by brine solution, dried over    anhydrous Na2SO4 and concentrated to afford the crude product. The    crude product was purified by column chromatography (silica gel, 2%    methanol in dichloromethane) to afford compound 5 as a pale yellow    solid. ¹H NMR (CDCl3, 400 MHz): o 8.26 (d, J=9.6 Hz, 2H), 7.37 (d,    J=9.8 Hz, 2H), 6.25 (s, 1H), 5.83 (t, J=8.4 Hz, 1H), 5.56 (s, 1H),    4.81 (d, J=12.8 Hz, 1H), 4.72 (d, J=12.4 Hz, 1H), 3.86 (m, 1H), 2.85    (m, 2H), 2.56 (m, 7H), 1.77 (m, 2H), 1.55 (s, 1H), 1.16 (t, J=13.2    Hz, 1H). ¹³C NMR (CDCl3, 100 MHz): o 169.1, 155.2, 152.2, 145.4,    138.6, 133.6, 132.8, 125.3, 121.5, 120.3, 80.8, 71.5, 63.1, 59.8,    42.7, 36.4, 25.6, 24.9, 23.9, 17.9 ppm.-   14. General synthetic procedure and analytical data for carbamate    derivatives of MMB: To the p-nitrophenyloxycarbonyl ester derivative    of MMB (5) (70 mg, 0.16 mmol) in dichloromethane (2 mL), the    appropriate amine (0.16 mmol) was added at 0° C. The reaction    mixture was stirred for 18 h at ambient temperature. When the    reaction was completed (monitored by TLC), water was added to the    reaction mixture and the aqueous mixture was extracted with    dichloromethane. The organic layer was washed with water, followed    by brine solution, dried over anhydrous Na₂SO₄ and concentrated to    afford the crude product. The crude product was purified by column    chromatography (silica gel, 5% methanol in dichloromethane) to    afford the carbamate analogs (6a-g) as white solids.    ((1aR,7aS,10aS,10bS,E)-1a-methyl-8-methylene-9-oxo-1a,2,3,6,7,    7a,8,9,10a,10b-decahydrooxireno[2′,3′:9,10]cyclodeca[1,2-b]furan-5-yl)methyl-4,4-difluoropiperidine-1-carboxylate    (6a): ¹H NMR (CDCl₃), 400 MHz): o 6.27 (d, J=2.8 Hz, 1H), 5.67 (t,    J=8.4 Hz, 1H), 5.56 (s, 1H), 4.69 (d, J=12.4 Hz, 1H), 4.52 (d, J=12    Hz, 1H), 3, 87 (t, J=9.6 Hz, 1H), 3.60 (br s, 4H), 2.87 (d, J=9.2    Hz, 2H), 2.50-2.16 (m, 6H), 1.96 (br s, 4H), 1.71 (t, J=10 Hz, 1H),    1.55 (s, 3H), 1.14 (t, J=12 Hz, 1H). ¹³C NMR (CDCl3, 100 MHz): o    169.4, 154.8, 138.7, 135.3, 129.9, 121.5, 120.5 (t, JCF=5.3 Hz, 1C),    81.1, 67.7, 63.4, 60.0, 42.7, 41.0, 36.7, 34.0, 25.8, 24.4, 23.9,    18.1 ppm. HRMS (ESI) m/z calcd for C₂₁H₂₈F₂NO₅ (M+H)⁺412.1930, found    412.1933.    ((1aR,7aS,10aS,10bS,E)-1a-methyl-8-methylene-9-oxo-1a,2,3,6,7,7a,8,9,10a,10b-decahydrooxireno[2′,3′:9,10]cyclodeca[1,2-b]furan-5-yl)methyl-(2-(pyrrolidin-1-yl)ethyl)carbamate    (6b): ¹H NMR (CDCl3, 400 MHz): a 6.22 (d, J=3.2 Hz, 1H), 5.65 (t,    J=7 Hz, 1H), 5.55 (s, 1H), 4.62 (d, J=11.6 Hz, 1H), 4.47 (d, J=12.4    Hz, 1H), 3.82 (t, J=9.6 Hz, 1H), 3.35 (s, 2H), 2.90-2.83 (m, 2H),    2.70 (s, 4H), 2.42 (d, J=9.6 Hz, 2H), 2.38-2.13 (m, 7H) 1.84 (s,    4H), 1.66 (t, J=12 Hz, 1H), 1.52 (s, 3H), 1.13 (t, J=11.6 Hz, 1H).    ¹³C NMR (CDCl₃, 100 MHz): δ 169.3, 156.1, 138.6, 135.3, 129.8,    120.1, 80.9, 67.0, 63.1, 59.8, 55.1, 53.8, 42.5, 38.9, 36.5, 25.6,    24.3, 23.6, 23.2, 17.8 ppm. HRMS (ESI) m/z calcd for C₂₂H₃₃N₂O₅    (M+H)⁺ 405.2384, found 405.2390.    ((1aR,7aS,10aS,10bS,E)-1a-methyl-8-methylene-9-oxo-1a,2,3,6,7,7a,8,9,10a,10b-decahydrooxireno[2′,3′:9,10]cyclodeca[1,2-b]furan-5-yl)methyl-(2-(pyridin-2-yl)ethyl)carbamate    (6c): ¹H NMR (CDCl₃, 400 MHz): δ 8.50 (s, 1H), 7.62 (t, J=7.2 Hz,    1H), 7.15 (d, J=7.6 Hz, 2H), 6.19 (s, 1H), 5.64 (t, J=8 Hz, 1H),    5.56-5.56 (m, 2H), 4.62 (d, J=12.4 Hz, 1H), 4.44 (d, J=12.8 Hz, 1H),    3.84 (t, J=9.2 Hz, 1H), 3.60 (d, J=6 Hz, 2H), 2.99-2.82 (m, 4H),    2.41-2.12 (m, 5H), 1.75 (s, 1H), 1.64 (d, J=10.4 Hz, 1H), 1.52 (s,    3H), 1.07 (t, J=13.6 Hz, 1H). ¹³C NMR (CDCl3, 100 MHz): o 169.3,    159.1, 156.0, 149.1, 138.6, 136.6, 135.5, 129.9, 123.4, 121.6,    120.2, 81.0, 67.0, 63.2, 59.8, 42.5, 40.1, 37.1, 36.6, 25.8, 24.4,    23.7, 17.9 ppm. HRMS (ESI) m/z calcd for C₂₃H₂₉N₂O₅ (M+H)⁺ 413.2071,    found 413.2073.    ((1aR,7aS,10aS,10bS,E)-1a-methyl-8-methylene-9-oxo-1a,2,3,6,7,7a,8,9,10a,10b-decahydrooxireno[2′,3′:9,10]-cyclodeca[1,2-b]furan-5-yl)-methyl(2-morpholino    ethyl)carbamate (6d): ¹H NMR (CDCl₃, 400 MHz): δ 6.11 (d, J=3.6 Hz,    1H), 5.58 (t, J=8 Hz, 1H), 5.43 (d, J=2.8 Hz, 1H), 5.06 (s, 1H),    4.53 (d, J=12.4 Hz, 1H), 4.34 (d, J=12 Hz, 1H), 3.74 (t, J=8.8 Hz,    1H), 3.56 (s, 4H), 3.16 (t, J=5.2 Hz, 2H), 2.78-2.72 (m, 2H), 2.32    (s, 8H), 2.21-2.00 (m, 4H), 1.55 (t, J=10.4 Hz, 1H), 1.41 (s, 3H),    1.01 (t, J=12 Hz, 1H). ¹³C NMR (CDCl3, 100 MHz): δ 169.2, 155.9,    138.7, 135.4, 130.2, 120.0, 80.9, 67.0, 66.7, 63.1, 59.8, 57.2,    53.1, 42.5, 37.0, 36.5, 25.7, 24.4, 23.7, 17.8 ppm. HRMS (ESI) m/z    calcd for C₂₂H₃₃N₂O₆ (M+H)⁺ 421.2333, found 421.2331.    ((1aR,7aS,10aS,10bS,E)-1a-methyl-8-methylene-9-oxo-1a,2,3,6,7,7a,8,9,10a,10b-decahydrooxireno[2′,3′:9,10]cyclodeca[1,2-b]furan-5-yl)methyl-(5-(methylthio)-1H-1,2,4-triazol-3-yl)carbamate    (6e): ¹H NMR (CDCl3, 400 MHz): δ 6.22 (s, 2H), 5.82 (t, J=8 Hz, 1H),    5.50 (s, 1H), 4.90 (d, J=12.4 Hz, 1H), 4.81 (d, J=12.4 Hz, 1H), 3.85    (t, J=9.6 Hz, 1H), 2.95 (s, 1H), 2.85 (d, J=9.2 Hz, 1H), 2.48-2.15    (m, 8H), 1.70-1.53 (m, 6H), 1.13 (t, J=12.4 Hz, 1H) ppm. ¹³C NMR    (CDCl3, 100 MHz): δ 169.1, 163.1, 157.4, 149.9, 138.5, 133.3, 132.7,    120.2, 80.7, 70.1, 62.9, 59.7, 42.4, 36.2, 25.6, 24.3, 23.7, 17.8,    13.5 ppm. HRMS (ESI) m/z calcd for C₁₉H₂₅N₄O₅S (M+H)⁺ 421.1540,    found 421.1524.    ((1aR,7aS,10aS,10bS,E)-1a-methyl-8-methylene-9-oxo-1a,2,3,6,7,7a,8,9,10a,10b-decahydrooxireno[2′,3′:9,10]cyclodeca[1,2-b]furan-5-yl)methyl-(3-(1H-imidazol-1-yl)-propyl)carbamate    (6f): ¹H NMR (CDCl₃, 400 MHz): δ 7.56 (s, 1H), 7.09 (s, 1H), 6.95    (s, 1H), 6.26 (d, J=3.6 Hz, 1H), 5.69 (t, J=8 Hz, 1H), 5.56 (d,    J=3.2 Hz, 1H), 4.85 (s, 1H), 4.64 (d, J=12.4 Hz, 1H), 4.51 (d,    J=12.4 Hz, 1H), 4.04 (t, J=7.2 Hz, 2H), 3.88 (t, J=9.2 Hz, 1H), 3.21    (d, J=6 Hz, 2H), 2.93-2.85 (m, 2H), 2.47-2.16 (m, 7H), 2.03 (t,    J=6.4 Hz, 1H) 1.70 (t, J=10.8 Hz, 1H), 1.55 (s, 3H), 1.15 (t, J=12.4    Hz, 1H). ¹³C NMR (CDCl3, 100 MHz): δ 169.5, 156.3, 138.9, 137.1,    135.3, 130.4, 129.6, 120.2, 118.8, 81.1, 67.3, 63.3, 60.0, 44.4,    42.7, 38.3, 36.7, 31.5, 25.8, 24.6, 23.8, 18.0 ppm. HRMS (ESI) m/z    calcd for C₂₂H₃₀N₃O₅ (M+H)⁺ 416.2180, found 416.2183.    ((1aR,7aS,10aS,10bS,E)-1a-methyl-8-methylene-9-oxo-1a,2,3,6,7,7a,8,9,10a,10b-decahydrooxireno[2′,3′:9,10]-cyclodeca[1,2-b]furan-5-yl)methyl-(3-morpholinopropyl)carbamate    (6 g) ¹H NMR (CDCl3, 400 MHz): δ 6.23 (s, 1H), 5.74 (s, 1H), 5.65    (t, J=8 Hz, 1H), 5.54 (s, 1H), 4.58 (d, J=12 Hz, 1H), 4.48 (d, J=16    Hz, 1H), 3.85 (t, J=9.2 Hz, 1H), 3.72 (s, 4H), 3.27 (s, 2H),    2.89-2.83 (m, 2H), 2.46-2.11 (m, 12H), 1.69 (t, J=12 Hz 3H), 1.52    (s, 3H), 1.11 (t, J=12 Hz, 1H). ¹³C NMR (CDCl₃, 100 MHz): δ 169.5,    156.3, 138.9, 135.7, 129.9, 120.4, 81.2, 67.0, 66.9, 63.4, 60.1,    57.4, 53.6, 42.7, 36.8, 25.9, 25.5, 24.6, 23.9, 18.1 ppm. HRMS (ESI)    m/z calcd for C₂₃H₃₅N₂O₆ (M+H)⁺ 435.2490, found 435.2482.-   15. Neelakantan, S.; Shama, N.; Guzman, M. L.; Jordan, C. T.;    Crooks, P. A. Bioorg. Med. Chem. Lett. 2009, 19, 4346.-   16. Boyd, M. R.; Paull, K. D. Drug Dev. Res. 1995, 34, 91.-   17. Acton, E. M.; Narayanan, V. L.; Risbood, P. A.; Shoemaker, R.    H.; Vistica, D. T.; Boyd, M. R. J. Med. Chem. 1994, 37, 2185.

TABLE 3 NCI five dose result for JVM 2-13 Log10 Concentration Time MeanOptical Densities Percent Growth Panel/Cell Zero Ctrl −8.0 −7.0 −8.0−5.0 −4.0 −8.0 −7.0 −6.0 −5.0 −4.0 GI50 TGI LC50 Leukemia CCRF-CEM 0.5222.168 2.231 2.319 2.052 0.584 0.306 104 109 93 4 −41 3.03E−61.21E−5 >1.00E−4  HL-60(TB) 1.473 3.000 2.840 3.095 3.103 1.511 0.827 90106 107 2 −44 3.50E−6 1.13E−5 >1.00E−4  K-562 0.204 1.321 1.323 1.2681.246 0.196 0.119 100 95 93 −4 −42 2.79E−6 9.11E−6 >1.00E−4  MOLT-40.650 1.937 1.938 2.138 1.868 0.739 0.331 100 116 95 7 −49  322E−61.33E−5 >1.00E−4  SR 0.388 1.416 1.600 1.364 1.160 0.500 0205 118 95 7511 −47  246E−6 1.54E−5 >1.00E−4  Non-Small Cell Lung Cancer A549/ATCC0.339 1.916 1.837 1.878 1.826 1.679 0.167 95 98 94 85 −51 1.81E−54.22E−5 9.85E−5 HOP-62 0.830 2.237 2.043 2.163 2.109 2069 0.190 86 95 9188 −77 1.70E−5  341E−5 6.85E−5 HOP-92 0.903 1.477 1.374 1.339 1.2550.928 0.157 82 76 61 4 −83 1.58E−6 1.12E−5 4.21E−5 NCI-H226 1084 2.5892.572 2.523 2482 1.866 0.716 99 96 93 52 −3 1.05E−5 4.02E−5 >1.00E−4  NCI-H 23 0609 1.871 1.841 1.868 1.915 1.330 0.158 98 100 104 57 −741.13E−5 2.72E−5 6.55E−5 NCI-H322M 0.787 1.705 1.754 1.814 1.760 1.6500.085 105 112 106 94 −89 1.74E−5  126E−5 6.11E−5 NCI-H460 0.278 2.8702.913 2.870 2.858 2.479 0.094 102 100 100 85 −66  170E−5 3.65E−5 7.81E−5NC I-H 522 0.886 2.041 2.030 2.100 1.536 0290 0.313 99 105 56 −67 −651.12E−6 2.86E−6 7.25E−6 Colon Cancer COLO 205 0.478 1.829 1.727 1.8461.694 0.156 0.118 92 101 90 −67 −75 1.79E−6 1.73E−6 7.75E−6 HCC-29980.687 2.060 2.049 2.134 2.115 2.003 0.156 99 105 104 96 −77 1.85E−53.60E−5 7.01E−5 HCT-116 0.307 2.533 2.413 2.486 2.183 0.428 0.025 95 9684 5 −92 2.72E−6 1.14E−5 3.70E−5 HCT-15 0.365 2.588 2.390 2.482 2.3290.585 0.091 91 95 88 10 −75 3.08E−6 1.31E−5 5.07E−5 HT29 0.241 1.2761.278 1.279 1.322 0.343 0.060 100 100 104 10 −75 3.76E−6 1.30E−5 5.04E−5KM 12 0.396 2.229 2.340 2.334 2.243 1.776 0.066 106 106 101 75 −831.44E−5 2.98E−5 6.16E−5 SW-620 0.365 2.850 2.845 2.795 2.426 0.545 0.094100 96 83 7 −74 2.72E−6 1.23E−5 5.03E−5 CNS Cancer SF-268 0.553 1.9471.909 1.998 1.890 1.241 0.121 97 104 96 49 −78 9.67E−6 2.44E−5 6.02E−5SF-295 0.825 3.013 2.805 2.910 2.925 2.883 1.518 90 95 96 94 325.08E−5 >1.00E−4  >1.00E−4  SF-539 0.584 1.973 1.866 1.842 1.853 0.7260.131 92 91 91 10 −78 3.23E−6 1.31E−5 4.84E−5 SNB-19 0.636 2.182 2.1482.128 2.116 1.957 0.182 98 97 96 85 −71 1.68E−5 1.51E−5 7.31E−5 SNB-750767 1.519 1.328 1.334 1.316 1.161 0.028 75 75 73 52 −96 1.04E−5 2.256−54.88E−5 U251 0487 2.142 2.111 2.089 2.042 2.026 0.077 98 97 94 93 −841.75E−5 1.35E−5 6.41E−5 Melanoma LOX IMVI 0.447 2.582 2.627 2.553 24621.540 0.073 102 99 94 51 −84 1.02E−5 2.39E−5 5.62E−5 MALME-3M 0.4470.721 0.729 0.718 0.630 0.295 0.194 103 99 67 −34 −57 1.47E−6 4.60E−65.06E−5 M14 0.555 2.098 1.961 2.029 1.953 1.199 0.100 91 96 91 42 −826.78E−6 a 17E−5 5.51E−5 MDA-MB- 0.539 2.535 2.426 2.479 2282 1.073 0.03995 97 87 27 −93 4.13E−6 1.67E−5 4.38E−5 435 SK-MEL-2 1.239 2.246 2.2802.373 2.372 2.123 0.302 103 113 113 88 −76 1.70E−5 3.44E−5 6.97E−5SK-MEL-28 0.552 1.525 1.505 1.524 1.429 0.685 0.106 98 100 90 14 −813.35E−6 1.40E−5 4.72E−5 8K-MEL-5 0.756 3.167 3.160 3.194 3.138 2.8120.066 100 101 99 85 −91 1.58E−5 3.04E−5 5.83E−5 UACC-257 1.097 2.3202.243 2.227 2.154 1.516 0.150 94 92 86 34 −86 4.99E−6 1.92E−5 4.99E−5UACC-62 0.531 2.451 2.361 2.353 2.227 1.156 0.078 95 95 88 33 −854.86E−6 1.89E−5 5.01E−5 Ovarian Cancer IGROVI 0.706 2.023 2.090 2.1052.042 1.136 0295 105 106 101 33 −58 5.59E−6 2.29E−5 8.12E−5 OVCAR-30.500 1.587 1.670 1.646 1.427 0.467 0.018 108 105 85 −7 −97 2.42E−68.46E−6 3.04E−5 OVCAR-5 0.744 1.531 1.408 1.430 1.389 1.165 0.105 84 8782 53 −86 1.06E−5 2.42E−5 5.52E−5 OVCAR-8 0.473 2.159 2.153 2.116 2.0341.016 0.118 100 97 93 32 −75 5.07E−6 2.00E−5 5.84E−5 NCI/ADR- 0.5942.034 2.079 2.128 2.073 1.956 0.659 103 107 103 95 43.12E−5 >1.00E−4  >1.00E−4  RES SK-OV-3 0.993 1.866 1.793 1.891 1.8421.843 0497 92 103 97 97 −50 2.10E−5 4.58E−5 >1.00E−4  Renal Cancer 786-00.540 2.168 1.944 1.992 2.001 0.917 0.138 86 89 90 23 −74 3.95E−61.73E−5 5.62E−5 A498 1.702 2.460 2.255 2.193 2.243 2.163 0.135 73 65 7161 −92 1.18E−5 2.50E−5 5.31E−5 ACHN 0.483 2.100 2.009 2.049 1.830 0.6100097 94 97 83 8 −80 2.76E−6 1.23E−5 4.56E−5 CAKI-1 0.661 2.943 2.6952.769 2.490 1.205 0.014 89 92 80 24 −98 3.43E−6 1.57E−5 4.04E−5 RXF 3931.123 1.717 1.703 1.633 1.573 1 A79 0.175 98 86 76 −4 −84 2.11E−68.93E−6 3.73E−5 SN12C 0.530 2.022 1.979 1.930 1.903 0.811 0.155 97 94 9219 −71 3.75E−6 1.62E−5 5.85E−5 TK-10 1.092 2,327 2.388 2.362 2.186 1.1480.066 105 103 89 5 −94 2.88E−6 1.11E−5 3.58E−5 UO-31 0.743 1.980 1.8691.874 1.755 1.004 0.140 91 91 82 21 −81 3.34E−6 1.61E−5 4.95E−5 ProstateCancer PC-3 0.611 1.933 1.891 1.885 1.860 1.665 0.167 97 96 94 80 −731.57E−5 3.33E−5 7.09E−5 DU-145 0.516 1.901 2.040 2.014 1.912 0.892 0.018110 108 101 27 −97 4.89E−6 1.66E−5 4.20E−5 Breast Cancer MCF7 0.3591.982 1.764 1.843 1.695 0.421 0.130 87 91 82 4 −64 2.58E−6 1.14E−56.25E−5 MDA-MB- 0.700 1.532 1.592 1.522 1.454 1.006 0.150 107 99 91 37−79 5.69E−6 2.08E−5 5.65E−5 231/ATCC HS 57BT 1.189 2.174 2.098 2.0422.065 1.917 0.996 92 87 89 74 −16 1.84E−5 6.60E−5 >1.00E−4  81-549 1.2662.258 2.089 2.143 2.151 1.606 0.051 83 88 89 34 −96 5.18E−6 1.83E−54.43E−5 T-47D 0.738 1.731 1.550 1.613 1.490 0.810 0.260 82 88 76 7 −652.38E−6 1.26E−5 6.24E−5 MDA-MB- 0.774 1.390 1.385 1.360 1.174 0.5040.247 99 95 65 −35 −68 1.41E−6 4.47E−6 2.85E−5 468

TABLE 4 NCI five dose result for JVM 2-26 Log10 Concentration Time MeanOptical Densities Percent Growth Panel/Cell Zero Ctrl −8.0 −7.0 −6.0−5.0 −4.0 −8.0 −7.0 −6.0 −5.0 −4.0 GI50 TGI LC50 Leukemia CCRF-CEM 0.5391.748 1.686 1.649 1.443 0.410 0.235 95 92 75 −24 −56 1.78E−6 5.72E−66.35E−5 HL-60(TB) 0.667 2.381 2.263 2.109 1.912 0.599 0.332 93 64 73 −10−50 1.88E−6 7.53E−6 9.87E−5 K-562 0.612 2.207 2.211 2.139 2.097 0.7600.355 100 96. 93 9 −42 3.27E−6 1.52E−5 >1.00E−4  MOLT-4 0.957 2.2292.288 2.258 2.136 1.246 0.475 105 102 93 23 −50 4.07E−6 1.04E−5 9.87E−5SR 0.252 1.050 0.953 0.928 0.843 0.256 0.116 88 65 74 . −54 2.12E−61.02E−5 8.39E−5 Non-Small Cell Lung Cancer A549/ATCC 0.398 1.497 1.4531.467 1.491 1.286 0.091 96 97 99 81 −77 1.57E−5 1.24E−5 6.72E−5 HOP-620.830 1.813 1.752 1.708 1.694 1.639 0.071 94 69 88 82 −91 1.53E−51.98E−5 5.77E−5 HOP-92 0.944 1.476 1.438 1.423 1.343 0.841 0.098 93 9075 −11 −90 1.96E−6 7.47E−6 3.14E−5 NCI-H226 0.851 2.268 2.184 2.1402.093 1.268 0.352 94 91 88 29 −59 4.43E−6 2.16E−0 7.98E−5 NC I-H 230.672 1.999 1.901 1.960 1.972 1.537 0.174 93 97 98 65 −74 1.28E−52.94E−5 6.71E−5 NCI-H322M 0.888 2.208 2.081 2.043 1.991 1.858 0.654 9067 84 73 −26 1.72E−5 5.44E−5 >1.00E−4  NCI-H460 0.386 3.181 3.242 3.2243.159 2.718 0.129 102 102 99 83 −67 1.67E−5 3.60E−5 7.75E−5 NC I-H 5221.103 2.123 2.106 2.032 1.626 0.334 0.298 98 91 71 −70 −73 1.41E−63.20E−6 7.24E−6 Colon Cancer COLO 205 0.527 1.454 1.469 1.433 1.3350.136 0.066 102 96 87 −74 −88 1.70E−6 3.47E−6 7.07E−6 HCC-2998 0.5681.899 1.844 1.873 1.954 1.571 0.082 96 96 104 75 −86 1.44E−5 1.94E−56.01E−5 HCT-116 0.207 1.669 1.643 1.603 1.406 0.167 −0.029 98 95 82 −20−100 2.07E−6 6.42E−6 2.39E−5 HCT-15 0.284 2.300 2.209 2.064 1.676 0.3340.029 96 BB 79 2 −90 2.39E−6 1.06E−5 3.70E−5 KM 12 0.508 2.616 2.5002494 2.562 2.222 0.089 95 94 97 81 −83 1.55E−5 3.13E−5 6.33E−5 SW-6200.314 2.517 2.504 2.413 2.064 0.299 0.051 99 95 79 −5 −84 2.23E−68.74E−6 3.73E−5 CNS Cancer SF-268 0.564 1.900 1.808 1.751 1.634 1.0710.095 93 69 95 38 −83 6.14E−6 2.06E−5 5.32E−5 SF-295 0.641 2.700 2.5492.430 2.496 2.236 0.193 93 67 90 77 −70 1.54E−5 3.35E−5 7.32E−5 SF-5390.954 2.543 2.413 2.323 2.2134 0.903 0.062 92 136 84 −5 −94 2.39E−68.70E−6 3.21E−5 SNB-19 0.705 2.275 2.158 2.202 2.093 1.816 0.069 93 9588 71 −90 1.35E−5 2.75E−5 5.63E−5 SNB-75 0.763 1.468 1.350 1.245 1.2260.958 −0.035 83 613. 66 28 −100 2.59E−6 1.65E−5 4.06E−5 U251 0.597 1.9531.891 1.908 1.944 1.805 0.088 95 97 99 89 −85 1.67E−5 3.24E−5 6.27E−5Melanoma LOX IMVI 0.316 2.170 2.021 2.035 2.042 0.441 0.027 92 93 93 7−91 3.15E−6 1.17E−5 3.78E−5 M14 0.452 1.609 1.588 1.520 1.479 0.7140.020 98 92 89 23 −96 3.85E−6 1.55E−5 4.11E−5 MDA-MB- 0.554 2.487 2.4402.244 2.167 0.809 0.030 98 67 83 13 −95 2.99E−6 1.32E−5 3.85E−5 435SK-MEL-2 1.069 2.062 2.070 2.097 2.046 1.639 0.145 101 104 98 57 −861.12E−5 2.51E−5 5.58E−5 SK-MEL-28 0.627 1.704 1.682 1.616 1.563 0.8670.028 98 92 89 22 −96 3.83E−6 1.55E−5 4.10E−5 8K-MEL-5 0.621 2.527 2.4292.443 2.363 1.650 0.003 95 96 92 54 −100 1.06E−5 2.25E−5 4.76E−5UACC-257 1.042 2.075 1.979 1.942 1.969 1.405 0.063 91 67 90 35 −945.34E−6 1.87E−5 4.56E−5 UACC-62 0.774 2.950 2.844 2.834 2.676 1.7780.025 95 95 87 46 −97 8.05E−6 1.10E−5 4.71E−5 Ovarian Cancer IGROVI0.763 2.283 2.288 2.256 2.315 1.765 0.264 100 96 102 66 −65 1.32E−53.17E−5 7.63E−5 OVCAR-3 0.513 1.577 1.556 1.533 1.370 0.390 −0.020 98 9680 −24 −100 1.96E−6 5.88E−6 2.20E−5 OVCAR-4 0.665 1.453 1.419 1.3201.226 0.715 0.069 96 63 71 6 −90 2.13E−6 1.16E−5 3.86E−5 OVCAR-5 0.6931.438 1.394 1.299 1.289 1.070 0.058 94 81 80 51 −92 1.01E−5 2.27E−55.09E−5 OVCAR-8 0.632 2.168 2.112 2.137 2.124 1.429 0.074 96 98 97 52−88 1.03E−5 1.35E−5 5.33E−5 NCI/ADR- 0.494 1.777 1.700 1.714 1.720 1.4890.298 94 95 96 78 −40 1.72E−5 4.58E−5 >1.00E−4  RES SK-OV-3 0.933 1.6391.592 1.676 1.603 1.566 0.624 93 105 95 90 −33 2.10E−5 5.37E−5 >1.00E−4 Renal Cancer 786-0 0.506 1.850 1.789 1.678 1.577 0.565 0.047 95 87 80 4−91 2.48E−6 1.11E−5 3.73E−5 A498 1.386 2.262 2.138 2.235 2.0613 1.8270.016 86 97 78 50 −99 1.01E−5 2.18E−5 4.70E−5 ACHN 0.448 1.772 1.7781.693 1.491 0.412 0.036 100 94 79 −8 −92 2.14E−6 8.06E−6 3.15E−5 CAKI-10.613 2.647 2.446 2.311 2.067 0.781 −0.029 90 83 71 8 −100 2.19E−61.19E−5 3.45E−5 RXF 393 0.735 1.328 1.310 1.307 1.227 0.694 0.079 97 9683 −6 −89 2.35E−6 8.65E−6 3.40E−5 SN12C 0.945 3.124 3.094 3.117 3.0271.954 0.157 99 100 96 46 −83 8.41E−6 2.27E−5 5.52E−5 TK-10 0.971 2.1512.050 2.057 1.905 0.818 −0.003 92 92 79 −16 −100 2.03E−6 6.82E−6 2.55E−5UO-31 0.831 2.274 2.040 2.053 1.908 0.956 0.171 84 65 75 9 −79 2.36E−61.25E−5 4.63E−5 Prostate Cancer PC-3 0.671 1.511 1.458 1.449 1.416 1.2280.075 94 93 89 66 −89 1.27E−5 1.67E−5 5.62E−5 DU-145 0.354 1.511 1.4831.478 1.394 0.478 −0.005 98 97 90 11 −100 3.19E6  1.25E−5 3.53E−5 BreastCancer MCF7 0.349 1.939 1.799 1.738 1.575 0.386 0.099 91 67 77 2 −722.30E−6 1.07E−5 5.08E−5 MDA-MB- 0.612 1.405 1.427 1.382 1.309 0.7830.113 103 97 88 22 −82 3.73E−6 1.62E−5 4.94E−5 231/ATCC HS 57BT 1.0092.130 2.052 2.029 1.977 1.392 0.550 93 91 86 34 −46 4.96E−62.68E−5 >1.00E−4  81-549 0.820 1.698 1.633 1.565 1.506 1.007 −0.018 9385 78 21 −100 3.12E−6 1.50E−5 3.87E−5 T-47D 0.857 1.527 1467 1.401 1.4200.786 0.246 91 81 84 −8 −71 2.34E−6 8.12E−6 4.59E−5 MDA-MB- 0.681 1.2311.202 1.161 0.898 0.345 0.130 95 87 39 −49 −81 6.01E−7 2.78E−6 1.05E−5468

TABLE 5 NCI five dose result for JVM 2-31 Log10 Concentration Time MeanOptical Densities Percent Growth Panel/Cell Zero Ctrl −8.0 −7.0 −6.0−5.0 −4.0 −8.0 −7.0 −6.0 −5.0 −4.0 GI50 TGI LC50 Leukemia CCRF-CEM 0.5391.748 1.802 1.830 1.614 0.555 0.295 104 107 89 1 −45 2.78E−61.07E−5 >1.00E−4  HL-60(TB) 0.667 2.381 2.637 2.496 2.430 0.816 0.342115 107 103 9 −49 3.64E−6 1.42E−5 >1.00E−4  K-562 0.612 2.207 2.2352.409 2.217 1.057 0.412 102 113 101 28 −33 4.96E−6 2.88E−5 >1.00E−4 MOLT-4 0.957 2.229 2.223 2.230 2.241 1.350 0.558 99 100 101 31 −425.33E−6 2.66E−5 >1.00E−4  SR 0.252 1.050 0.994 1.023 0.659 0.300 0.14493 97 76 6 −43 2.35E−6 1.33E−5 >1.00E−4  Non-Small Cell Lung CancerA549/ATCC 0.398 1.497 1.505 1.563 1.539 1.309 0.160 101 106 104 83 −601.70E−5 3.80E−5 8.52E−5 HOP-62 0.830 1.813 1.711 1.724 1.762 1.768 0.33590 91 95 95 −60 1.96E−5 4.12E−5 8.67E−5 HOP-92 0.944 1.476 1.421 1.4311.421 0.944 0.138 90 92 90 . −85 2.77E−6 9.99E−6 3.85E−5 NCI-H226 0.8512.268 2.157 2.103 2.064 1.326 0.381 92 88 87 34 −55 4.92E−6 2.39E−58.72E−5 NC I-H 23 0.672 1.999 1.998 2.023 2.010 1.571 0.205 100 102 10168 −70 1.35E−5 3.11E−5 7.20E−5 NCI-H322M 0.888 2.208 2.242 2.246 2.3122.308 0.837 103 103 UM 108 −6 3.22E−5 8.90E−5 >1.00E−4  NCI-H460 0.3863.181 3.221 3.238 3.176 2.859 0.246 101 102 100 88 −36 2.03E−55.12E−5 >1.00E−4  NC I-H 522 1.103 2.123 2.143 2.131 1.956 0.408 0.405102 101 84 −63 −63 1.70E−6 3.72E−6 8.15E−6 Colon Cancer COLO 205 0.5271.454 1.414 1.523 1.465 0.399 0.132 96 107 101 −24 −75 2.56E−6 6.39E−63.20E−5 HCC-2998 0.568 1.899 2.026 1.980 2.024 1.665 0.087 110 106 10982 −85 1.56E−5 3.11E−5 6.19E−5 HCT-116 0.207 1.669 1.600 1.654 1.4710.271 0.005 98 99 86 4 −98 2.78E−6 1.10E−5 3.40E−5 HCT-15 0.284 2.3002.078 2.096 1.893 0.422 0.071 89 90 80 7 −75 2.56E−6 1.21E−5 4.95E−5HT29 0.508 2.616 2.631 2.692 2.664 2.465 0.198 101 104 102 93 −611.90E−5 4.01E−5 8.48E−5 SW-620 0.314 2.517 2.491 2.473 2.220 0.495 0.13099 98 87 8 −59 2.93E−6 1.33E−5 7.40E−5 CNS Cancer SF-268 0.564 1.9001.910 1.938 1.932 1.183 0.996 101 103 102 46 −65 8.59E−6 2.60E−5 7.30E−5SF-295 0.641 2.700 2.265 2.501 2.446 2.133 0.265 84 90 BB 72 −59 1.48E−53.57E−5 8.58E−5 SF-539 0.954 2.543 2.355 2.422 2.315 0.884 0.933 88 9266 −7 −86 2.42E−6 8.33E−6 3.48E−5 SNB-19 0.705 2.275 2.234 2.194 2.2051.848 0.496 97 95 96 73 −30 1.67E−5 5.13E−5 >1.00E−4  SNB-75 0.763 1.4681.239 1.316 1.266 1.064 0.016 68 78 74 43 −98 5.84E−6 2.01E−5 4.56E−5U251 0.597 1.953 1.976 2.015 2.009 1.853 0.091 102 105 104 93 −851.74E−5 3.33E−5 6.37E−5 Melanoma LOX IMVI 0.316 2.170 2.138 2.173 2.0750.529 0.041 98 100 95 11 −87 3.45E−6 1.31E−5 4.21E−5 M14 0.452 1.6091.504 1.593 1.512 0.775 0.052 91 99 92 28 −88 4.50E−6 1.74E−5 4.67E−5MDA-MB- 0.554 2.487 2.305 2.439 2.307 1.095 0.201 91 98 91 28 −644.45E−6 2.02E−5 7.09E−5 435 SK-MEL-2 1.069 2.062 2.096 2.163 2.123 1.7950.298 103 110 106 73 −72 1.44E−5 3.19E−5 7.04E−5 SK-MEL-28 0.627 1.7041.615 1.679 1.617 0.987 0.020 92 98 92 33 −97 5.21E−6 1.81E−5 4.37E−58K-MEL-5 0.621 2.527 2.424 2.413 2.337 1.420 0.106 95 94 90 42 −836.80E−6 2.17E−5 5.45E−5 UACC-257 1.042 2.075 2.096 2.114 2.022 1.5310.281 102 104 95 47 −73 8.79E−6 2.47E−5 6.43E−5 UACC-62 0.774 2.9502.869 2.871 2.778 1.676 0.122 96 96 92 41 −84 6.78E−6 2.14E−5 5.34E−5Ovarian Cancer IGROVI 0.763 2.283 2.430 2.485 2.525 2.074 0.275 110 113116 86 −64 1.74E−5 3.75E−5 8.07E−5 OVCAR-3 0.513 1.577 1.627 1.692 1.5430.606 0.016 105 111 97 9 −97 3.40E−6 1.21E−5 3.60E−5 OVCAR-4 0.665 1.4531.339 1.395 1.332 0.880 0.215 86 93 85 27 −68 4.01E−6 1.94E−5 6.51E−5OVCAR-5 0.693 1.438 1.319 1.378 1.384 1.205 0.150 84 92 93 69 −781.34E−5 2.93E−5 6.41E−5 OVCAR-8 0.632 2.168 2.205 2.238 2.177 1.4190.230 102 105 101 51 −64 1.02E−5 2.79E−5 7.60E−5 NCI/ADR- 0.494 1.7771.786 1.789 1.754 1.635 0.521 101 101 98 89 22.81E−5 >1.00E−4  >1.00E−4  RES SK-OV-3 0.933 1.639 1.622 1.623 1.6751.701 0.746 98 98 105 109 −20 2.86E−5 6.99E−5 >1.00E−4  Renal Cancer786-0 0.506 1.850 1.700 1.769 1.649 0.659 0.079 89 94 85 11 −84 2.99E−61.31E−5 4.37E−5 A498 1.386 2.262 2.180 2.227 2.256 1.961 0.093 91 96 9966 −93 1.25E−5 2.59E−5 5.34E−5 ACHN 0.448 1.772 1.698 1.752 1.625 0.6070.103 94 99 89 12 −77 3.21E−6 1.36E−5 4.96E−5 CAKI-1 0.613 2.647 2.3372.416 2.262 1.084 0.013 85 89 81 23 −98 3.44E−6 1.55E−5 4.02E−5 RXF 3930.735 1.328 1.279 1.286 1.063 0.731 0.130 92 93 55 −1 −82 1.24E−69.75E−6 4.02E−5 SN12C 0.945 3.124 3.034 3.024 3.039 2.082 0.293 96 95 9652 −69 1.04E−5 2.70E−5 6.97E−5 TK-10 0.971 2.151 2.076 2.098 2.003 0.9590.054 94 95 87 −1 −94 2.64E−6 9.68E−6 3.33E−5 UO-31 0.831 2.274 2.2122.276 2.301 1.331 0.236 96 100 102 35 −72 5.91E−6 2.12E−5 6.26E−5Prostate Cancer PC-3 0.671 1.511 1.427 1.447 1.482 1.243 0.146 90 92 9668 −78 1.33E−5 2.92E−5 6.41E−5 DU-145 0.354 1.511 1.499 1.578 1.4190.559 0.015 99 106 92 18 −96 3.68E−6 1.43E−5 3.94E−5 Breast Cancer MCF70.349 1.405 1.366 1.343 1.300 0.879 0.147 95 92 67 34 −76 4.92E−61.20E−5 7.63E−5 MDA-MB- 0.612 2.130 2.070 2.049 2.039 1.520 0.976 95 9392 46 −3 8.01E−6 2.03E−5 5.79E−5 231/ATCC HS 57BT 1.009 1.698 1.5591.636 1.512 1.086 0.036 84 93 79 30 −96 3.92E−6 8.57E−5 >1.00E−4  81-5490.820 1.527 1.419 1.495 1.472 0.858 0.403 84 95 92 −53 2.86E−6 1.74E−54.34E−5 T-47D 0.857 1.748 1.802 1.830 1.614 0.555 0.295 104 107 89 1 −452.78E−6 1.00E−5 8.79E−5 MDA-MB- 0.681 1.231 1.193 1.178 0.957 0.5470.173 93 90 50 −20 −75 1.01E−6 5.23E−6 3.57E−5 468

TABLE 6 NCI five dose result for JVM 2-35 Log10 Concentration Time MeanOptical Densities Percent Growth Panel/Cell Zero Ctrl −8.0 −7.0 −6.0−5.0 −4.0 −8.0 −7.0 −6.0 −5.0 −4.0 GI50 TGI LC50 Leukemia CCRF-CEM 0.5391.630 1.548 1.564 1.427 0.454 0.300 93 96 81 −16 −44 2.10E−66.137E−6  >1.00E−4  HL-60(TB) 0.667 2.232 2.130 1.962 1.798 0.551 0.32094 83 72 −17 −52 1.77E−6 6.40E−6 8.70E−5 K-562 0.612 1.972 1.989 1.9122.065 1.026 0.408 101 96 107 30 −33 5.55E−6 3.00E−5 >1.00E−4  MOLT-40.957 2.230 2.258 2.283 2.130 1.405 0.485 102 104 92 35 −49 5.50E−62.61E−5 >1.00E−4  SR 0.252 0.960 0.822 0.797 0.779 0.281 0.139 80 77 744 −45 2.22E−6 1.21E−5 >1.00E−4  Non-Small Cell Lung Cancer A549/ATCC0.398 1.393 1.307 1.339 1.348 1.226 0.109 91 95 95 83 −73 1.63E−53.42E−5 7.16E−5 HOP-62 0.830 1.799 1.753 1.718 1.653 1.630 0.766 95 9285 83 −8 2.29E−5 8.21E−5 >1.00E−4  HOP-92 0.944 1.450 1.443 1.414 1.3860.947 0.089 98 93 87 −91 2.69E−6 1.01E−5 3.58E−5 NCI-H226 0.851 2.2382.136 2.112 2.084 1.663 0.381 93 91 89 58 −55 1.19E−5 3.27E−5 8.99E−5 NCI-H 23 0.672 1.987 1.906 1.963 1.946 1.688 0.300 94 98 97 77 −55 1.60E−53.82E−5 9.10E−5 NCI-H322M 0.888 2.082 1.956 2.049 1.974 1.896 0.998 8997 91 84 9 2.87E−5 >1.00E−4  >1.00E−4  NCI-H460 0.386 3.144 3.161 3.1523.099 2.859 0.249 101 100 98 90 −35 2.07E−5 5.21E−5 >1.00E−4  NC I-H 5221.103 2.486 2.312 2.342 2.099 0.525 0.351 87 90 72 −52 −68 1.50E−63.79E−6 9.57E−6 Colon Cancer COLO 205 0.527 1.449 1.445 1.460 1.3850.352 0.023 100 101 93 −33 −96 2.19E−6 5.46E−6 1.86E−5 HCC-2998 0.5681.916 1.857 1.918 1.966 1.694 0.085 96 100 104 84 −85 1.58E−5 3.13E−56.19E−5 HCT-116 0.207 1.707 1.683 1.521 1.449 0.292 −0.009 98 88 83 6−100 2.66E−6 1.13E−5 3.36E−5 HCT-15 0.284 2167 2.081 2.020 1.829 0.4690.049 95 92 82 10 −83 2.78E−6 1.28E−5 4.43E−5 HT29 0.508 2.469 2.4242.446 2.432 2.283 0.361 98 99 98 91 −29 2.18E−5 5.72E−5 >1.00E−4  SW-6200.314 2.371 2.343 2.315 2.190 0.658 0.069 99 97 91 17 −78 3.58E−61.50E−5 5.06E−5 CNS Cancer SF-268 0.564 1.874 1.784 1.769 1.770 1.3360.166 93 92 92 59 −71 1.17E−5 2.85E−5 6.93E−5 SF-295 0.641 2.579 2.4182.357 2.384 2.187 0.717 92 89 90 80 4 2.47E−5 >1.00E−4  >1.00E−4  SF-5390.954 2.493 2.480 2.357 2.410 1.239 0.070 99 91 95 19 −93 3.86E−61.47E−5 4.13E−5 SNB-19 0.705 2.102 2.032 2.005 1.958 1.765 0.565 95 9390 76 −20 1.86E−5 6.20E−5 >1.00E−4  SNB-75 0.763 1.416 1.258 1.204 1.1701.055 0.080 76 68 62 45 90 4.96E−6 2.15E−5 5.07E−5 U251 0.597 1.8881.785 1.787 1.847 1.811 0.302 92 92 97 94 −49 2.03E−5 4.52E−5 >1.00E−4 Melanoma LOX IMVI 0.316 2.113 2.065 2.033 2.054 0.876 0.036 97 96 97 31−09 5.16E−6 1.82E−5 4.75E−5 M14 0.452 1.594 1.558 1.469 1.410 0.7300.052 97 89 84 24 −88 3.71E−6 1.64E−5 4.56E−5 MDA-MB- 0.554 2.261 2.2152.095 2.095 0.960 0.066 97 90 90 24 −88 4.03E−6 1.63E−5 4.57E−5 435SK-MEL-2 1.069 2.082 2.145 2.174 2.024 1.819 0.447 106 109 94 74 −581.52E−5 3.63E−5 8.66E−5 SK-MEL-28 0.627 1.722 1.662 1.659 1.561 0.9490.084 95 94 85 29 −87 4.27E−6 1.79E−5 4.83E−5 8K-MEL-5 0.621 2.466 2.4332.450 2.306 1.712 0.061 98 99 91 59 −90 1.15E−5 2.49E−5 5.38E−5 UACC-2571.042 1.970 1.907 1.838 1.896 1.519 0.153 93 86 92 51 −85 1.02E−52.38E−5 5.52E−5 UACC-62 0.774 2.793 2.714 2.670 2.501 1.590 0.041 96 9486 40 −95 6.13E−6 1.99E−5 4.66E−5 Ovarian Cancer IGROVI 0.763 2.2172.225 2.222 2.237 1.946 0.419 101 100 101 81 −45 1.77E−54.40E−5 >1.00E−4  OVCAR-3 0.513 1.558 1.533 1.620 1.531 0.578 0.018 98106 97 6 −96 3.31E−6 1.15E−5 3.53E−5 OVCAR-4 0.665 1.394 1.365 1.2961.282 0.923 0.027 96 87 85 35 −96 5.04E−6 1.86E−5 4.46E−5 OVCAR-5 0.6931.435 1.333 1.309 1.290 1.199 0.082 86 83 80 68 −88 1.31E−5 2.73E−55.70E−5 OVCAR-8 0.632 2.030 2.052 2.055 2.077 1.543 0.303 102 102 103 65−52 1.35E−5 3.60E−5 9.60E−5 NCI/ADR- 0.494 1.711 1.681 1.722 1.747 1.5170.462 97 101 103 84 −7 2.37E−5 8.46E−5 >1.00E−4  RES SK-OV-3 0.933 1.6191.629 1.628 1.612 1.590 0.856 102 101 99 96 −8 2.75E−5 8.33E−5 >1.00E−4 Renal Cancer 786-0 0.506 1.875 1.798 1.730 1.637 0.623 0.032 94 89 83 9−94 2.75E−6 1.21E−5 3.73E−5 A498 1.386 2.331 2.140 2.266 2.138 2.0440.149 80 93 80 70 −89 1.33E−5 2.74E−5 5.66E−5 ACHN 0.448 1.659 1.6921.638 1.524 0.608 0.044 103 98 89 13 −90 3.26E−6 1.34E−5 4.09E−5 CAKI-10.613 2.386 2.258 2.133 1.978 1.036 0.006 93 86 77 24 −99 3.22E−61.56E−5 3.99E−5 RXF 393 0.735 1.268 1.260 1.286 1.206 0.805 0.130 98 10388 13 −82 3.23E−6 1.37E−5 4.58E−5 SN12C 0.945 3.005 2.884 2.883 2.8722.236 0.549 94 94 94 63 −42 1.32E−5 3.97E−5 >1.00E4   TK-10 0.971 2.1012.121 2.123 2.041 1.189 0.110 102 102 95 19 −89 3.92E−6 1.51E−5 4.38E−5UO-31 0.831 2.168 1.952 1.961 1.949 1.269 0.098 84 85 84 33 −88 4.58E−61.86E−5 4.83E−5 Prostate Cancer PC-3 0.671 1.474 1.431 1.406 1.360 1.2480.144 95 91 86 72 −79 1.40E−5 3.00E−5 6.45E−5 DU-145 0.354 1.471 1.4831.468 1.427 0.501 0.013 101 100 96 13 −96 3.59E−6 1.32E−5 3.77E−5 BreastCancer MCF7 0.349 1.810 1.684 1.595 1.599 0.482 0.106 91 85 86 9 −702.92E−6 1.30E−5 5.63E−5 MDA-MB- 0.612 1.319 1.328 1.313 1.241 0.8830.131 101 99 89 38 −79 5.86E−6 2.13E−5 5.69E−5 231/ATCC HS 57BT 1.0092.051 1.969 1.982 1.905 1.640 0.830 92 93 86 61 −18 1.36E−55.93E−5 >1.00E−4  81-549 0.820 1.746 1.699 1.599 1.576 1.193 0.014 95 8482 40 −98 5.82E−6 1.95E−5 4.48E−5 T-47D 0.857 1.560 1.620 1.537 1.4780.905 0.283 108 97 88 7 −67 2.95E−6 1.24E−5 5.88E−5 MDA-MB- 0.681 1.2331.208 1.195 1.013 0.666 0.203 95 93 60 −2 −70 1.46E−6 9.20E−6 5.04E−5468

TABLE 7 NCI five dose result for JVM 2-40 Log10 Concentration Time MeanOptical Densities Percent Growth Panel/Cell Zero Ctrl −8.0 −7.0 −6.0−5.0 −4.0 −8.0 −7.0 −6.0 −5.0 −4.0 GI50 TGI LC50 Leukemia CCRF-CEM 0.5391.823 1.728 1.762 1.363 0.442 0.268 93 95 64 −18 −50 1.49E−6 6.04E−69.80E−5 HL-60(TB) 0.667 2.208 2.161 2.075 1.717 0.590 0.300 97 91 68 −12−55 1.69E−6 7.15E−6 7.63E−5 K-562 0.612 2.135 2.155 2.127 2.082 0.9300.424 101 99 97 21 −31 4.12E−6 2.53E−5 >1.00E−4  MOLT-4 0.957 2205 2.2702.254 2.110 1.240 0.531 105 104 92 23 −45 4.05E−6 2.17E−5 >1.00E−4  SR0.252 0.944 0.874 0.837 0.769 0.280 0.156 90 85 75 4 −38 2.24E−61.25E−5 >1.00E−4  Non-Small Cell Lung Cancer A549/ATCC 0.398 1.494 1.4241.372 1.467 1.152 0.072 94 89 98 69 −82 1.33E−5 2.86E−5 6.13E−5 HOP-620.830 1.828 1.766 1.748 1.694 1.608 0.139 94 92 87 78 −83 1.49E−53.04E−5 6.22E−5 HOP-92 0.944 1.454 1.416 1.402 1.374 0.858 0.066 93 9084 −9 −93 2.33E−6 7.99E−6 3.07E−5 NCI-H226 0.851 2.222 2.140 2.110 2.0431.447 0.378 94 92 87 43 −56 7.07E−6 2.74E−5 8.77E−5 NC I-H 23 0.6722.005 1.929 1.936 1.985 1.526 0.279 94 95 98 64 −59 1.30E−5 3.33E−58.52E−5 NCI-H322M 0.888 2.102 1.959 2.003 2.016 1.822 0.822 88 92 93 77−7 2.09E−5 8.15E−5 >1.00E−4  NCI-H460 0.386 3.129 3.179 3.148 3.0762.588 0.168 102 101 98 80 −56 1.67E−5 3_86E−5  8.97E−5 NC I-H 522 1.1032.131 1.983 1.985 1.680 0.199 0.244 86 86 54 −82 −78 1.07E−6 2.50E−65.82E−6 Colon Cancer COLO 205 0.527 1.415 1.402 1.419 1.321 0.409 0.04498 100 89 −22 −92 2.25E−6 6.29E−0 2.50E−5 HCC-2998 0.568 1.820 1.7611.802 1.865 1.483 0.056 95 99 104 73 −90 1.38E−5 2.80E−5 5.68E−5 HCT-1160.207 1.676 1.650 1.533 1.304 0.271 −0.014 98 90 75 4 −100 2.24E−61.10E−5 3.32E−5 HCT-15 0.284 2.118 2.106 1.967 1.701 0.240 0.028 99 9277 −16 −90 1.96E−6 6.78E−6 2.89E−5 HT29 0.508 2.581 2.504 2.506 2.5532.223 0.122 96 96 99 83 −76 1.61E−5 3.32E−5 6.86E−5 SW-620 0.314 2.4112.410 2.425 1.921 0.443 0.073 100 101 77 6 −77 2.39E−6 1.19E−5 4.74E−5CNS Cancer SF-268 0.564 1.956 1.868 1.665 1.831 1.173 0.148 94 93 91 44−74 7.36E−6 2.36E−5 6.28E−5 SF-295 0.641 2.913 2.468 2.356 2.453 1.9990.097 92 87 92 69 −85 1.32E−5 2.80E−5 5.93E−5 SF-539 0.954 2.439 2.3122.230 2.264 0.904 0.075 91 86 88 −5 −92 2.56E−6 8.79E−6 3.27E−5 SNB-190.705 2.099 2.021 2.029 1.929 1.682 0.102 94 95 88 70 −86 1.35E−52.82E−5 5.91E−5 SNB-75 0.763 1.447 1.321 1.226 1.189 0.993 0.005 82 6862 34 −99 2.69E−6 1.79E−5 4.25E−5 U251 0.597 1.931 1.855 1.881 1.8541.810 0.009 94 96 94 91 −98 1.64E−5 3.02E−5 5.55E−5 Melanoma LOX IMVI0.316 2.003 1.955 1.938 1.898 0.509 0.047 97 96 94 11 −85 3.40E−61.31E−5 4.33E−5 M14 0.452 1.565 1.517 1.391 1.3313 0.623 0.048 96 84 8016 −89 2.91E−6 1.41E−5 4.22E−5 MDA-MB- 0.554 2.352 2.283 2.156 2.1020.943 0.140 96 89 86 22 −75 3.63E−6 1.68E−5 5.54E−5 435 SK-MEL-2 1.0692.007 2.038 2.032 1.946 1.568 0.214 103 103 93 53 −80 1.06E−5 2.51E−55.95E−5 SK-MEL-28 0.627 1.655 1.676 1.618 1.490 0.863 0.869 102 96 84 23−89 3.59E−6 1.60E−5 4.48E−5 8K-MEL-5 0.621 2.422 2.393 2.324 2.230 1.4250.064 98 95 89 45 −90 7.58E−6 2.15E−5 5.06E−5 UACC-257 1.042 2.094 1.9871.924 1.909 1.420 0.079 90 84 82 36 −92 4.98E−6 1.90E−5 4.67E−5 UACC-620.774 2.751 2.637 2.646 2.515 1.537 0.041 94 95 88 39 −95  593E−61.95E−5 4.62E−5 Ovarian Cancer IGROVI 0.763 2.185 2.223 2.242 2.3171.910 0.311 103 104 109 81 −59 1.66E−5 3.77E−5 8.58E−5 OVCAR-3 0.5131.632 1.624 1.637 1.502 0.499 −0.003 99 100 88 −3 −100 2.63E−6 9.31E−63.06E−5 OVCAR-4 0.665 1.334 1.377 1.302 1.264 0.348 0.213 99 89 83 25−68 3.76E−6 1.87E−5 6.41E−5 OVCAR-5 0.693 1.438 1.381 1.326 1.303 0.9760.050 92 85 82 38 −93 5.31E−6 1.95E−5 4.70E−5 OVCAR-8 0.632 1.996 1.9761.944 2.032 1.266 0.180 99 96 103 46 −72 8.95E−6 2.47E−5 6.56E−5NCI/ADR- 0.494 1.652 1.657 1.645 1.663 1370 0.328 100 99 101 76 −341.72E−5 4.92E−5 >1.00E−4  RES SK-OV-3 0.933 1.619 1.609 1.627 1.5601.566 0.684 99 101 91 92 −27 2.27E−5 5.97E−5 >1.00E−4  Renal Cancer786-0 0.506 2.042 1.999 1.920 1.807 0.777 0.032 97 92 85 18 −94 3.29E−61.44E−5 4.85E−5 A498 1.386 2.307 2.276 2.231 2.100 1.902 0.033 97 92 7756 −98 1.09E−5 2.31E−5 4.90E−5 ACHN 0.448 1.678 1.713 1.668 1.502 0.4110.043 103 99 86 −8 −91 2.40E−6 8.17E−6 3.22E−5 CAKI-1 0.613 2.436 2.3162.194 1.944 1.005 −0.802 93 87 73 21 −100 2.79E−6 1.50E−5 3.88E−5 RXF393 0.735 1.252 1.240 1.255 1.089 0.636 0.101 98 100 68 −13 −86 1.68E−66.85E−6 3.17E−5 SN12C 0.945 2.949 2.894 2.925 2.819 1.729 0.274 97 99 9439 −71 6.31E−6 2.26E−5 6.44E−5 TK-10 0.971 2.021 1.963 2.003 1.854 1.008−0.816 94 98 84 3 −100 2.65E−6 1.08E−5 3.29E−5 UO-31 0.831 2.171 1.9802.014 1.968 1.046 0.085 86 88 85 16 −90 3.21E−6 1.42E−5 4.21E−5 ProstateCancer PC-3 0.671 1.522 1.482 1.459 1.456 1.194 0.117 95 93 92 61 −831.20E−5 2.67E−5 5.94E−5 DU-145 0.354 1.463 1.523 1.517 1.311 0.545 0.002105 105 86 17 −99 3.35E−6 1.40E−5 3.77E−5 Breast Cancer MCF7 0.349 1.8331.676 1.552 1.447 0.455 0.088 89 81 74 7 −75 2.28E−6 1.22E−5 4.98E−5MDA-MB- 0.612 1.313 1.306 1.302 1.179 0.785 0.081 99 98 81 25 −873.54E−6 1.66E−5 4.67E−5 231/ATCC HS 57BT 1.009 2.100 2.054 2.071 1.9901.344 0.794 96 97 90 31 −21 4.72E−6 3.89E−5 >1.00E−4  81-549 0.820 1.6431.597 1.518 1.574 1.123 0.008 94 85 92 37 −99 5.74E−6 1.87E−5 4.35E−5T-47D 0.857 1.497 1.454 1.451 1.3137 0.902 0.297 93 93 83 7 −65 2.70E−61.25E−5 6.13E−5 MDA-MB- 0.681 1.178 1.147 1.122 0.867 0.414 0.155 94 8938 −39 −77 5.74E−7 3.09E−6 1.92E−5 468

TABLE 8 NCI five dose result for JVM 2-44 Log10 Concentration Time MeanOptical Densities Percent Growth Panel/Cell Zero Ctrl −8.0 −7.0 −6.0−5.0 −4.0 −8.0 −7.0 −6.0 −5.0 −4.0 GI50 TGI LC50 Leukemia CCRF-CEM 0.5222.393 2.265 2.250 2.185 0.689 0.393 93 92 89 9 −25 3.06E−61.84E−5 >1.00E−4  HL-60(TB) 1.473 2.782 2.812 2.607 2.594 1.432 0.925102 87 B6 −3 −37 2.53E−6 9.30E−6 >1.00E−4  K-562 0.204 1.116 1.141 1.0301.109 0.394 0.152 103 91 99 21 −25 4.25E−6 2.82E−5 >1.00E−4  MOLT-40.650 1.823 1.889 1.794 1.734 1.062 0.453 106 98 92 35 −30 5.49E−63.43E−5 >1.00E−4  SR 0.388 1.310 1.227 1.224 1.105 0.534 0.332 91 91 7816 −14 2.81E−6 3.33E−5 >1.00E−4  Non-Small Cell Lung Cancer A549/ATCC0.339 1.794 1.778 1.802 1.748 1.536 0.267 99 101 97 82 −21 2.05E−56.23E−5 >1.00E−4  HOP-62 0.830 2.250 2.193 2.046 2.174 2.007 0.936 96 8695 83 7 2.73E−5 >1.00E−4  >1.00E−4  HOP-92 0.903 1.417 1.394 1.345 1.3070.995 0.116 95 86 79 18 −87 2.95E−6 1.48E−5 4.43E−5 NCI-H226 1.084 2.6222.561 2.533 2.540 2.002 0.601 96 94 95 60 −45 1.24E−5 3.73E−5 >1.00E−4 NCI-H23 0.609 1.872 1.849 1.838 1.872 1.347 0.244 98 97 100 58 −601.18E−5 3.12E−5 8.24E−5 NCI-H322M 0.787 1.710 1.649 1.624 1.650 1.4340.569 93 91 93 70 −25 1.62E−5 5.44E−5 >1.00E−4  NCI-H460 0.278 2.7982.830 2.825 2.741 2.401 0.202 101 101 98 84 −28 2.03E−55.67E−5 >1.00E−4  NCI-H522 0.886 2.020 1.900 1.925 1.747 0.338 0.194 8992 76 −62 −78 1.54E−6 3.55E−5 8.20E−6 Colon Cancer COLO 205 0.478 1.7781.784 1.715 1.790 0.767 0.159 100 95 101 22 −67 4.44E−6 1.76E−5 6.48E−5HCC-2998 0.667 2.809 1.968 1.999 2.049 1.871 0.178 97 99 103 90 −731.75E−5 3.55E−5 7.19E−5 HCT-116 0.307 2.263 2.298 2.250 2.231 0.5980.061 102 99 98 15 −80 3.79E−6 1.43E−5 4.80E−5 HCT-15 0.365 2.556 2.4352.370 2.210 0.643 0.108 94 92 84 13 −71 3.01E−6 1.42E−5 5.66E−5 HT290.241 1.155 1.216 1.248 1.268 0.502 0.873 107 110 112 28 −70 5.54E−61.95E−5 6.20E−5 KM12 0.396 2.171 2.117 2.151 2.184 1.680 0.105 97 99 10172 −74 1.42E−5 3.13E−5 6.89E−5 SW-620 0.365 2.749 2.698 2.683 2.5990.753 0.080 98 97 94 16 −78 3.67E−6 1.49E−5 5.83E−5 CNS Cancer SF-2680.553 1.862 1.843 1.839 1.625 1.432 0.188 99 9B 97 67 −66 1.35E−53.19E−5 7.57E−5 SF-295 0.825 2.997 2.920 2.707 2.913 2.724 1.767 96 8796 87 43 7.07E−5 >1.00E−4  >1.00E−4  SF-539 0.584 1.953 1.915 1.7991.761 1.049 0.121 97 89 87 34 −79 5.01E−6 1.99E−5 5.51E−5 SNB-19 0.6362.191 2.149 2.075 2.030 1.860 0.513 97 93 90 79 −19 1.96E−56.35E−5 >1.00E−4  SNB-75 0.767 1.507 1.343 1.274 1.330 1.112 0.183 78 6876 47 −76 7.65E−6 2.40E−5 6.12E−5 U251 0.487 2.044 2.013 2.003 2.0021.893 0.206 98 97 97 90 −58 1.87E−5 4.08E−5 8.87E−5 Melanoma LOX IMVI0.447 2.542 2.424 2.419 2452 1.794 0.051 94 94 96 64 −89 1.24E−5 2.63E−55.59E−5 MALME-3M 0.447 0.708 0.702 0.680 0.705 0.461 0.168 98 89 99 5−63 3.33E−6 1.20E−5 6.54E−5 M14 0.555 1.968 1.953 1.848 1.877 1.2290.178 99 91 94 48 −68 8.89E−6 2.58E−5 6.99E−5 MDA-MB- 0.539 2.359 2.3962.240 2.253 1.343 0.109 102 93 94 44 −80 7.64E−6 2.27E−5 5.75E−5 435SK-MEL-2 1.239 2.100 2.082 2.037 2.148 1.984 0.382 98 93 106 87 −691.72E−5 3.60E−5 7.53E−5 SK-MEL-28 0.552 1.492 1.458 1.424 1.424 0.9500.108 96 93 93 42 −80 7.03E−6 2.21E−5 5.65E−5 8K-MEL-5 0.756 3.194 3.1163.182 3.118 2.878 0.067 97 100 97 87 −91 1.61E−5 3.06E−5 5.87E−5UACC-257 1.097 2.228 2.160 2.135 2.046 1.662 0.150 94 92 84 50 −869.93E−6 2.32E−5 5.41E−5 UACC-62 0.531 2.355 2.369 2.330 2.153 1.2840.089 101 99 89 41 −83 6.56E−6 2.14E−5 5.41E−5 Ovarian Cancer IGROVI0.706 1.825 1.866 1.888 1.902 1.363 0.249 104 106 107 59 −65 1.11E−52.99E−5 7.60E−5 OVCAR-3 0.500 1.526 1.551 1.594 1.396 0.743 0.031 102107 87 24 −94 3.86E−6 1.59E−5 4.23E−5 OVCAR-5 0.744 1.477 1.415 1.4041.400 1.240 0.201 91 90 89 68 −73 1.34E−5 3.03E−5 6.86E−5 OVCAR-8 0.4732.831 2.052 2.055 1.997 1.385 0.184 101 102 98 59 −61 1.11E−5 3.06E−58.06E−5 NCI/ADR- 0.594 2.895 2.060 2.049 2.094 1.819 0.606 98 97 100 821 2.46E−5 >1.00E−4  >1.00E−4  RES SK-OV-3 0.993 1.886 1.885 1.808 1.8921.852 1.032 100 91 101 96 4 3.18E−5 >1.00E−4  >1.00E−4  Renal Cancer786-0 0.540 2.173 2.113 2.022 2.074 1.194 0.194 96 91 94 40 −64 6.53E−62.42E−5 7.23E−5 A498 1.702 2.586 2.357 2.301 2.296 2.150 0.967 74 68 6751 −43 1.02E−5 3.47E−5 >1.00E−4  ACHN 0.483 1.990 2.010 1.961 1.8830.773 0.112 101 9B 93 19 −77 3.83E−6 1.59E−5 5.26E−5 CAKI-1 0.661 2.9532.814 2.649 2.593 1.287 0.032 94 87 84 27 −95 4.00E−6 1.67E−5 4.28E−5RXF 393 1.123 1.719 1.646 1.692 1.644 1.871 0.329 88 96 87 −5 −712.55E−6 8.91E−6 4.86E−5 SN12C 0.530 1.978 1.940 1.898 1.835 0.932 0.18997 94 90 28 −64 4.40E−6 2.80E−5 6.97E−5 TK-10 1.092 2.260 2.185 2.1982.166 1.338 0.069 94 95 92 21 −94 3.91E−6 1.53E−5 4.16E−5 UO-31 0.7432.000 1.731 1.737 1.744 0.983 0.127 79 79 80 19 −83 3.08E−6 1.54E−54.76E−5 Prostate Cancer PC-3 0.611 1.876 1.916 1.899 1.917 1.854 0.340103 102 103 98 −44 2.18E−5 4.89E−5 >1.00E−4  DU-145 0.516 1.858 1.8391.845 1.844 0.750 0.835 99 99 99 17 −93 3.98E−6 1.44E−5 4.87E−5 BreastCancer MCF7 0.359 1.932 1.767 1.666 1.725 0.561 0.116 89 83 87 13 −683.14E−6 1.44E−5 6.01E−5 MDA-MB- 0.700 1.569 1.619 1.568 1.525 1.1530.200 106 106 95 52 −72 1.04E−5 2.64E−5 6.70E−5 231/ATCC HS 57BT 1.1892.200 2.099 2.057 2.096 1.827 1.235 90 86 90 63 51.67E−5 >1.00E−4  >1.00E−4  81-549 1.266 2.125 2.028 1.951 1.985 1.5220.180 89 80 84 30 −86 4.21E−6 1.81E−5 4.90E−5 T-47D 0.738 1.646 1.6641.593 1.660 0.946 0.323 102 94 102 23 −56 4.52E−6 1.94E−5 8.23E−5MDA-MB- 0.774 1.354 1.328 1.377 1.156 0.737 0.228 95 104 66 −5 −711.87E−6 8.56E−6 4.87E−5 468

TABLE 9 NCI five dose result for JVM 2-50 Log10 Concentration Time MeanOptical Densities Percent Growth Panel/Cell Zero Ctrl −8.0 −7.0 −6.0−5.0 −4.0 −8.0 −7.0 −6.0 −5.0 −4.0 GI50 TGI LC50 Leukemia CCRF-CEM 0.4582.041 2.004 2.068 1.773 0.467 0.256 98 102 83 1 −44 2.52E−61.03E−5 >1.00E−4  HL-60(TB) 1.062 3.014 3.130 3.166 3.231 1.245 0.557106 109 111 9 −48 3.99E−6  146E−5 >1.00E−4  K-562 0.164 1.071 1.2471.159 1.074 0.376 0.123 119 110 100 23 −25 4.51E−6 3.02E−5 >1.00E−4 MOLT-4 0.736 2.441 2.549 2.662 2.500 1.469 0.452 106 114 103 43 −397.65E−6 3.368-5 >1.00E−4  RPMI-8226 1.080 2.466 2.435 2.420 2.369 1.5310.554 98 97 93 33 −49 5.14E−6 2.51E−5 >1.00E−4  SR 0.462 1.926 1.9191.922 1.798 0.728 0.326 100 100 91 18 −30 3.67E−6  240E−5 >1.00E−4 Non-Small Cell Lung Cancer A549/ATCC 0.464 2.347 2.272 2.200 2.278 2.2230.221 96 92 96 93 3 3.02E−5 >1.00E−4  >1.00E−4  HOP-62 0.764 2.176 2.0062.035 2.059 2.011 0.890 88 90 92 88 9 3.04E−5 >1.00E−4  >1.00E−4  HOP-921.261 1.863 1.802 1.792 1.625 1.341 0.155 90 86 94 13 −88 3.49E−61.35E−5 4.23E−5 NCI-H226 1.048 2.573 2.467 2.508 2.439 2.071 0.664 93 9691 67 −37 1.46E−5 4.43E−5 >1.00E−4  NC I-H 23 0.701 2.013 1.990 2.0452.012 1.579 0.329 98 102 100 67 −53 1.38E−5 3.61E−5 9.43E−5 NCI-H322M0.835 1.954 2.013 2.055 2.011 2.059 1.196 105 109 105 109 325.88E−5 >1.00E−4  >1.00E−4  NCI-H460 0.321 3.278 3.287 3.272 3.220 3.2090.560 100 100 98 98 8 3.40E−5 >1.00E−4  >1.00E−4  NCI-H522 1.088 2.3822.351 2.431 2.342 0.479 0.333 98 104 97 −56 −69 2.03E−6 4.30E−6 9.13E−6Colon Cancer COLO 205 0.512 1.688 1.640 1.756 1.785 0.761 0.104 96 106108 21 −80 4.87E−6 1.62E−5 5.07E−5 HCC-2998 0.753 2.226 2.203 2.3102.309 2.293 0.230 98 106 136 105 −70 2.06E−5 3.99E−5 7.72E−5 HCT-1160.241 2.134 1.995 2.068 1.940 0.534 0.061 93 96 90 15 −75 3.43E−61.48E−5 5.32E−5 HCT-15 0.420 2.719 2.560 2.614 2.584 0799 0.122 93 95 9416 −71 3.70E−6 1.54E−5 5.75E−5 HT29 0.313 1.673 1.657 1.729 1.789 1.0910.167 99 104 109 57 −47 1.17E−5 3.55E−5 1.00E−4 SW-620 0.382 2.199 2.2412.275 2.226 2.065 0.109 102 104 101 93 −71 1.82E−5 3.67E−5 7.40E−5 CNSCancer SF-268 0.664 2.092 2.077 2.060 2.096 1.955 0.329 99 99 100 90 −511.93E−5 4.38E−5 9.91E−5 SF-295 0.791 3.033 2.773 2.819 2.918 2.865 1.76788 90 95 92 44 7.37E−5 1.06E−4 >1.00E−4  SF-539 1.057 2.897 2.809 2.8012.764 2.059 0.160 95 95 93 54 −85 1.08E−5 2.46E−5 5.62E−5 SNB-19 0.7022.347 2.337 2.235 2.261 2.088 1.018 99 93 95 84 193.26E−5 >1.00E−4  >1.00E−4  SNB-75 1.019 1.900 1.633 1.713 1.719 1.6170.815 70 79 79 68 −20 1.60E−5 5.92E−5 >1.00E−4  U251 0.618 2.493 2.4282.408 2.331 2.379 0.458 97 95 91 94 −26 2.33E−5 6.08E−5 >1.00E−4 Melanoma LOX IMVI 0.548 2.843 2.845 2.887 2.791 2.093 0.067 100 102 9867 −88 1.29E−5 2.72E−5 5.71E−5 MALME-3M 0891 1.174 1.209 1.225 1.2230.970 0.230 107 111 110 58 −67 1.15E−5 2.91E−5 7.33E−5 M14 0429 1.9141.774 1.864 1.795 1.257 0.184 91 97 92 56 −57 1.12E−5 3.11E−5 8.83E−5MDA-MB- 0.580 2.663 2.480 2.577 2.477 1.413 0.091 91 96 91 40 −846.37E−6 2.10E−5 5.20E−5 435 SK-MEL-2 0.921 1.582 1.622 1.689 1.679 1.5000.428 106 116 115 83 −54 1.85E−5 4.18E−5  944E−5 SK-MEL-28 0.748 2.1932.127 2.249 2.176 1.449 0.292 95 104 99 48 −61 9.33E−6 2.77E−5 7.94E−58K-MEL-5 0.749 3.114 3.160 3.112 3.122 2.744 0.494 102 100 100 84 −341.95E−5 5.15E−5 >1.00E−4  UACC-257 0.950 2.114 2.052 2.662 1.934 1.4580.257 95 90 65 44 −73 7.00E−6 2.37E−5 6.35E−5 UACC-62 1.123 3.071 2.9372.935 3.005 2.326 0.178 93 93 97 62 −84 1.20E−5 2.65E−5 5.83E−5 OvarianCancer IGROVI 0.500 1.624 1.563 1.687 1.722 1.056 0.321 95 106 109 49−36 9.79E−6 1.80E−5 >1.00E−4  OVCAR-3 0.539 1.818 1.857 1.900 1.6541.047 0.037 103 106 103 40 −93 6.27E−6 1.99E−5 4.73E−5 OVCAR-5 0.6291.690 1.578 1.598 1.528 1.348 0.288 89 91 85 68 −54 1.40E−5 1.59E−59.24E−5 OVCAR-8 0553 2.273 2.238 2.198 2.219 1.615 0.415 98 96 97 62 −251.37E−5 5.15E−5 >1.00E−4  NCI/ADR- 0.588 1.976 2.086 2.149 2.061 2.0400.814 108 113 106 105 16 4.15E−5 >1.00E−4  >1.00E−4  RES SK-OV-3 0.8431.738 1.864 1.766 1.769 1.789 1.047 92 103 103 106 234.70E−5 >1.00E−4  >1.00E−4  Renal Cancer 786-0 0.295 2.473 2.295 2.4162.419 1.699 0.158 91 97 97 59 −74 1.17E−5 2.78E−5 6.64E−5 A498 1.1721.902 1.716 1.670 1.613 1.593 0.883 74 68 60 58 −25 1.24E−55.01E−5 >1.00E−4  ACHN 0.458 2.153 2.087 2.176 2.144 1.182 0.166 96 10199 43 84 7.44E−6 2.52E−5 7.11E−5 CAKI-1 0.812 3.058 2.804 2.859 2.7701.895 0.285 89 91 87 48 −65 8.99E−6 2.67E−5 7.38E−5 RXF 393 0.730 1.4861.421 1.436 1.473 0.882 0.234 91 93 98 20 −68 4.14E−6 1.69E−5 6.25E−5SN12C 0.737 2.770 2.640 2.591 2.595 2.222 0.649 94 91 31 73 −12 1.86E−57.22E−5 >1.00E−4  TK-10 1.011 1.853 1.852 1.662 1.933 1.473 0.090 100103 110 55 −91 1.08E−5  236E−5 5.23E−5 UO-31 0.844 2107 2.041 2.0932.060 1.694 0.296 95 99 96 67 −65 1.35E−5 3.23E−5 7.71E−5 ProstateCancer PC-3 0.632 2.247 2.209 2.141 2.193 2.149 0.500 98 93 97 94 −212.41E−5 6.57E−5 >1.00E−4  DU-145 0.442 1.790 1.896 1.902 1.689 1.2450.035 108 106 107 60 −92 1.16E−5 2.47E−5 5.28E−5 Breast Cancer MCF70.461 2.392 2.132 2.176 2.091 0.761 0.189 87 89 84 16 −59 3.16E−61.61E−5 7.55E−5 MDA-MB- 0.769 1841 1.840 1.749 1.828 1.450 0.263 100 9199 63 −66 1.27E−5 1.10E−5 7.55E−5 231/ATCC HS 578T 0.962 2.180 2.0782.036 2.067 1.962 1.232 92 88 91 82 22 3.43E−5 >1.00E−4  >1.00E−4 BT-549 0.866 1.736 1.604 1.659 1.585 1.046 0.078 85 91 83 21 −91 3.26E−61.53E−5 4.29E−5 T-47D 1.033 2.130 2.011 2.060 2.013 1.213 0.474 89 95 6916 −54 3.46E−6 1.71E−5 8.74E−5 MDA-MB-468 0.768 1.419 1.407 1.358 1.2050.674 0.255 98 91 67 −12 −67 1.64E−6 7.01E−6 4.91E−5

TABLE 10 NCI five dose result for JVM 2-57 Log10 Concentration Time MeanOptical Densities Percent Growth Panel/Cell Zero Ctrl −8.0 −7.0 −6.0−5.0 −4.0 −8.0 −7.0 −6.0 −5.0 −4.0 GI50 TGI LC50 Leukemia CCRF-CEM 0.4581.876 1.831 1.771 1.289 0.327 0.216 97 93 59 −29 −53 1.25E−6 4.69E−67.63E−5 HL-60(TB) 1.062 2.916 2.849 2.751 2.613 0.950 0.478 96 91 84 −11−55 2.28E−6 7.73E−6 7.72E−5 K-562 0.164 0.918 0.910 3.859 0.861 0.2840.939 99 92 92 16 −16 3.58E−6 3.20E−5 >1.00E−4  MOLT-4 0.736 2.356 2.3152194 2.316 0.869 0.446 97 90 98 8 −39 3.40E−6 1.49E−5 >1.00E−4 RPMI-8226 1.080 2.427 2.447 2.340 2.253 1.170 0.512 101 94 87 7 −532.89E−6 1.30E−5 9.03E−5 SR 0.462 1.909 1.920 1.857 1.573 0.520 0.253 10196 77 4 −45 2.33E−6 1.21E−5 >1.00E−4  Non-Small Cell Lung CancerA549/ATCC 0.464 2.271 2.270 2.245 2.178 1.746 0.056 100 99 95 71 −881.35E−5 2.80E−5 5.77E−5 HOP-62 0.764 2.149 2.087 1.951 2044 1.768 0.11095 86 92 72 −86 1.39E−5 2.87E−5 5.95E−5 HOP-92 1.261 1.941 1.792 1.7881.740 1.143 0.061 92 91 83 −9 −95 2.26E−6 7.90E−6 2.97E−5 NCI-H226 1.0482.621 2.502 2.644 2.403 1.816 0.506 92 101 86 49 −52 9.29E−6 3.06E−59.61E−5 NCI-H 3 0.701 2.022 1.945 1.959 1.917 1.101 0.227 94 95 92 30−68 4.79E−6 2.04E−5 6.61E−5 NCI-H322M 0.835 1.912 1.888 1.853 1.8641.675 0.693 98 94 97 78 −17 1.97E−5 6.62E−5 >1.00E−4  NCI-H460 0.3213.194 3.274 3.281 3.230 2.548 0.111 103 103 101 78 −65 1.56E−5 3.49E−57.80E−5 NCI-H522 1.088 2.392 2.252 2.218 1.969 0.293 0.279 89 87 68 −73−74 1.33E−6 3.02E−6 6.85E−6 Colon Cancer COLO 205 0.512 1.745 1.7801.707 1.685 0.470 0.033 103 97 95 −8 −94 2.73E−6 8.33E−6 3.08E−5HCC-2998 0.753 2.226 2.143 2.692 2.328 1.716 0.145 94 91 107 65 −811.27E−5 2.80E−5 6.16E−5 HCT-116 0.241 1.936 1.972 1.810 1.730 0.2940.005 102 93 88 3 −98 2.80E−6 1.07E−5 3.36E−5 HCT-15 0.420 2.699 2.6532.638 2.289 0.520 0.071 98 97 82 4 −83 2.58E−6 1.12E−5 4.18E−5 HT290.313 1.618 1.628 1.570 1.673 0.590 0.085 101 96 104 21 −73 4.50E−61.68E−5 5.70E−5 KM12 0.382 2.260 2.227 2.211 2.240 1.757 0.032 98 97 9973 −92 1.38E−5 2.78E−5 5.59E−5 SW-620 0.259 2.533 2.482 2.513 1.7440.386 0.052 98 99 65 6 −80 1.80E−6 1.16E−5 4.47E−5 CNS Cancer SF-2680.664 2.133 2.011 1.981 2.017 1.627 0.182 92 90 92 66 −73 1.30E−52.98E−5 6.86E−5 SF-295 0.791 3.004 2.929 2.779 2.849 2.467 0.555 97 9093 76 −30 1.75E−5 5.21E−5 >1.00E−4  SF-539 1.057 2.929 2.864 2.756 2.7031.478 0.084 97 91 88 22 −92 3.80E−6 1.57E−5 4.29E−5 SNB-19 0.702 2.2282.144 2.149 2.112 1.834 0.437 94 95 92 74 −38 1.64E−5 4.59E−5 >1.00E−4 SNB-75 1.019 1.932 1.780 1.713 1.730 1.519 0.599 83 76 78 55 −41 1.12E−53.72E−5 >1.00E−4  U251 0.618 2.380 2.366 2.323 2.231 2.049 −0.003 99 9792 81 −100 1.49E−5 2.81E−5 5.30E−5 Melanoma LOX IMVI 0.548 2.845 2.7602.719 2.657 1.037 0.050 96 95 92 21 −91 3.92E−6 1.55E−5 4.32E−5 MALME-3M0.691 1.194 1.171 1.168 1.166 0.818 0.164 95 95 94 25 −76 4.38E−61.77E−5 5.50E−5 M14 0.429 1.806 1.795 1.660 1.629 0.795 0.145 99 89 8727 −66 4.10E−6 1.93E−5 6.67E−5 MDA-MB- 0.580 2.715 2.683 2.570 2.5311.268 0.109 99 93 91 32 −81 5.01E−6 1.92E−5 5.31E−5 435 SK-MEL-2 0.9211.538 1.516 1.532 1.531 1.246 0.279 96 99 99 53 −70 1.05E−5 2.69E−56.90E−5 SK-MEL-28 0.748 2.190 2.163 2.054 2.057 1.099 0.154 98 91 91 24−79 4.11E−6 1.72E−5 5.20E−5 8K-MEL-5 0.749 3.184 3.179 3.134 3.104 2.1030.200 100 98 97 56 −73 1.11E−5 2.70E−5 6.60E−5 UACC-257 0.950 2.0491.982 1.985 1.755 1.213 0.088 94 94 73 24 −91 2.96E−6 1.62E−5 4.41E−5UACC-62 1.123 2.979 2.972 2.967 2.727 1.773 0.160 100 99 86 35 −865.11E−6 1.95E−5 5.05E−5 Ovarian Cancer IGROVI 0.500 1.597 1.598 1.6111.620 0.587 0.213 100 101 102 8 −57 3.58E−6 1.32E−5 7.70E−5 OVCAR-30.539 1.826 1.810 1.831 1.646 0.633 0.002 99 100 86 7 −100 2.87E−61.17E−5 3.43E−5 OVCAR-5 0.629 1.593 1.526 1.440 1.460 0.861 0.060 93 8486 24 −90 3.82E−6 1.62E−5 4.43E−5 OVCAR-8 0.553 2.237 2.242 2.240 2.1091.063 0.134 100 160 92 30 −76 4.82E−6 1.93E−5 5.72E−5 NCI/ADR- 0.5882.030 1.959 2.043 2.017 1.458 0.428 95 101 99 60 −27 1.31E−54.89E−5 >1.00E−4  RES SK-OV-3 0.843 1.709 1.721 1.625 1.753 1.632 0.620101 90 105 91 −26 2.24E−5 5.96E−5 >1.00E−4  Renal Cancer 786-0 0.5952.440 2.364 2.253 2.306 1.287 0.070 96 90 93 38 −88 5.94E−6 1.99E−54.96E−5 A498 1.172 1.903 1.691 1.687 1.653 1.409 0.123 71 70 66 32 −902.97E−6 1.84E−5 4.74E−5 ACHN 0.458 2.108 2.078 1.995 1.851 0.572 0.08098 93 84 7 −83 2.78E−6 1.19E−5 4.33E−5 CAKI-1 0.812 3.093 2.993 2.8382.674 1.050 0.026 96 89 82 10 −97 2.78E−6 1.25E−5 3.66E−5 RXF 393 0.7301.446 1.437 1.497 1.270 0.714 0.173 99 107 75 −2 −76 2.12E−6 9.35E−64.41E−5 SN12C 0.737 2.702 2.626 2.648 2.560 1.288 0.300 96 97 93 28 −594.57E−6 2.09E−5 7.81E−5 TK-10 1.011 1.775 1.726 1.758 1.744 0.963 0.05394 98 96 −5 −95 2.86E−6 8.97E−6 3.18E−5 UO-31 0.844 2.031 1.847 1.8921.812 0.922 0.059 84 88 82 7 −93 2.63E−6 1.16E−5 3.69E−5 Prostate CancerPC-3 0.632 2.370 2.330 2.327 2.303 1.797 0.188 98 97 96 67 −70 1.33E−53.08E−5 7.11E−5 DU-145 0.442 1.776 1.831 1.812 1.679 0.691 0.014 104 10393 19 −97 3.78E−6 1.45E−5 3.93E−5 Breast Cancer MCF7 0.461 2.313 2.1972.093 2.001 0.527 0.114 94 88 83 4 −75 2.61E−6 1.11E−5 4.77E−5 MDA-MB-0.769 1.837 1.902 1.722 1.690 1.096 0.178 106 89 86 31 −77 4.48E−61.93E−5 5.62E−5 231/ATCC HS 578T 0.962 2.162 2.053 2.070 2.006 1.7471.050 91 92 87 65 7 1.84E−5 >1.00E−4  >1.00E−4  BT-549 0.866 1.999 2.0561.839 1.710 0.865 0.035 105 86 74 −96 2.13E−6 9.96E−6 3.31E−5 T-47D1.033 1.950 1.897 1.819 1.775 0.995 0.204 94 86 81 −4 −80 2.32E−69.04E−6 4.02E−5 MDA-MB- 0.768 1.447 1.447 1.441 1.159 0.633 0.273 100 9958 −18 −65 1.26E−6 5.83E−6 4.90E−5 468

TABLE 11 NCI five dose result for JVM 2-66 Log10 Concentration Time MeanOptical Densities Percent Growth Panel/Cell Zero Ctrl −8.0 −7.0 −6.0−5.0 −4.0 −8.0 −7.0 −6.0 −5.0 −4.0 GI50 TGI LC50 Leukemia CCRF-CEM 0.4581.932 1.881 1.885 1.058 0.295 0.216 97 97 41 −36 −53 6.82E−7 3.41E−66.76E−5 HL-60(TB) 1.062 2.871 2.813 2.575 2.482 0.920 0.538 97 84 79 −13−49 2.04E−6 7.15E−6 >1.00E−4  K-562 0.164 0.893 0.920 0.856 0.842 02590.147 104 95 93 13 −10 3.45E−6 3.61E−5 >1.00E−4  MOLT-4 0.736 2.2812.195 2.043 2.050 0.535 0.447 94 85 85 −27 −39 2.05E−6 5.71E−6 >1.00E−4 RPMI-8226 1.080 2.543 2.510 2.503 2.272 0.811 0.583 98 97 81 −25 −461.98E−6 5.83E−6 >1.00E−4  SR 0.462 1.851 1.768 1.677 1.292 0.417 0.28894 87 60 −10 −38 1.38E−6 7.24E−6 >1.00E−4  Non-Small Cell Lung CancerA549/ATCC 0.464 2.188 2.148 2.143 2.072 1.450 0.124 98 97 93 57 −731.13E−5 2.74E−5 6.62E−5 HOP-62 0.764 2.310 2.322 2.168 2.202 1.861 0.099101 92 93 71 −87 1.36E−5 2.81E−5 5.83E−5 HOP-92 1.261 1.968 1.932 1.9081.748 0.657 0.070 95 92 69 −48 −94 1.45E−6 3.89E−6 1.11E−5 NCI-H2261.048 2.504 2.527 2.354 2.313 0.533 0.301 102 90 87 −49 −71 1.87E−54.35E−6 1.09E−5 NCI-H23 0.701 1.883 1.802 1.835 1.766 0.654 0.210 93 9698 −7 −70 2.59E−6 8.51E−6 4.82E−5 NCI-H322M 0.835 1.887 1.846 1.8791.911 1.553 0.066 96 99 102 68 −92 1.30E−5 2.66E−5 5.46E−5 NCI-H4600.321 3.213 3.228 3.232 3.184 2.250 0.100 100 101 99 67 −69 1.33E−53.10E−5 7.26E−5 NCI-H522 1.088 2.354 2.243 2.256 1.898 0.202 0.215 91 9264 −81 −80 1.25E−6 2.75E−6 6.08E−6 Colon Cancer COLO 205 0.512 1.8061.838 1.752 1.822 0.195 0.036 102 96 101 −62 −93 2.06E−6 4.17E−6 8.44E−6HCC-2998 0.753 2.081 2.029 1.966 2.092 1.243 0.173 96 91 101 37 −776.24E−6 2.11E−5 5.79E−5 HCT-116 0.241 1.981 1.963 1.858 1.459 0.085−0.001 99 93 70 −65 −100 1.41E−6 3.30E−6 7.75E−6 HCT-15 0.420 2.5532.551 2.426 1.919 0.210 0.058 100 94 70 −50 −86 1.47E−6 3.84E−6 1.00E−5HT29 0.313 1.578 1.538 1.592 1.599 0.338 0.051 97 101 102 2 −84 3.30E−61.05E−5 4.03E−5 KM12 0.382 2.216 2.269 2.164 2.194 1.234 0.059 103 97 9946 −85 8.55E−6 2.26E−5 5.45E−5 SW-620 0.259 2.368 2.345 2.311 1.6780.161 0.037 99 97 67 −38 −86 1.46E−6 4.37E−6 1.79E−5 CNS Cancer SF-2680.664 2.085 2.021 1.988 2.018 1.436 0.104 95 93 95 54 −84 1.07E−52.47E−5 5.65E−5 SF-295 0.791 2.935 2.831 2.738 2.746 2.132 0.035 95 9191 63 −96 1.20E−5 2.49E−5 5.15E−5 SF-539 1.057 2.809 2.734 2.547 2.6430.568 0.132 96 85 90 −46 −88 1.98E−6  459E−6 1.23E−5 SNB-19 0.702 2.1082.006 1.980 1.956 1.627 0.145 93 91 89 66 −79 1.28E−5 2.84E−5 6.27E−5SNB-75 1.019 2.025 1.894 1.774 1.815 1.443 0.056 87 75 79 42 −95 6.13E−62.03E−5 4.72E−5 U251 0.618 2.376 2.306 2.313 2.236 1.903 0.008 96 96 9273 −99  136E−5 2.66E−5 5.21E−5 Melanoma LOX IMVI 0.548 2.661 2.575 2.5152.496 0.390 0.062 96 93 92 −29 −89 2.23E−6 5.77E−6 2.25E−5 MALME-3M0.691 1.242 1.236 1.191 1.155 0.421 0.196 99 91 84 −39 −72 1.90E−64.82E−6 2.16E−5 M14 0.429 1.830 1.771 1.653 1.621 0.535 0.063 96 87 85 8−85  284E−6  121E−5 4.17E−5 MDA-MB- 0.580 2.886 2.844 2.672 1.263 1.0340.281 98 91 30 20 −52 4.64E−7 1.89E−5 9.51E−5 435 SK-MEL-2 0.921 1.5381.540 1.533 1.526 0.876 0.145 100 99 98 −5 −84 2.93E−6 8.95E−6 3.70E−5SK-MEL-28 0.748 2.072 2.096 1.986 1.971 0.645 0.123 102 94 92 −14 −842.51E−6 7.42E−6 3.30E−5 8K-MEL-5 0.749 2.949 2.935 2.928 2.745 1.2020.031 99 99 91 21 −96 3.81E−6 1.50E−5 4.03E−5 UACC-257 0.950 2.089 2.0232.043 1.648 0.959 0.099 94 96 79 1 −90 2.34E−6 1.02E−5 3.65E−5 UACC-621.123 2.887 2.830 2.780 2.638 0.848 0.064 97 94 86 −24 −94 2.11E−66.00E−6 2.32E−5 Ovarian Cancer IGROVI 0.500 1.595 1.671 1.656 1.4500.430 0.198 107 106 87 −14 −60 2.31E−6 7.26E−6 5.97E−5 OVCAR-3 0.5391.852 1.872 1.793 1.593 0.258 0.006 101 95 80 −52 −99 1.69E−6 4.03E−69.62E−6 OVCAR-5 0.629 1.500 1.467 1.413 1.488 0.814 0.106 96 90 99 21−83 4.25E−6 1.60E−5 4.81E−5 OVCAR-8 0.553 2.226 2.189 2.156 2.075 0.5590.080 98 96 91 −86 2.83E−6 1.01E−5 3.85E−5 NCI/ADR- 0.588 1.877 1.8801.859 1.871 0.981 0.205 100 99 99 30 −65 5.22E−6 2.08E−5 6.95E−5 RESSK-OV-3 0.843 1.835 1.831 1.760 1.837 1.688 0.145 100 92 100 85 −831.62E−5 3.22E−5 6.38E−5 Renal Cancer 786-0 0.595 2.491 2.435 2.314 2.3510.921 0.115 97 91 93 17 −81 3.67E−6 1.50E−5 4.86E−5 A498 1.172 1.8241.718 1.647 1.601 1.022 0.078 84 73 66 −13 −93 1.59E−6 6.87E−6 2.89E−5ACHN 0.458 1.966 2.005 1.859 1.593 0.346 0.079 103 93 75 −25 −83 1.79E−65.68E−6 2.74E−5 CAKI-1 0.812 3.200 3.140 2.988 2.767 0.635 0.028 97 9182 −22 −97 2.03E−6 6.16E−6 2.38E−5 RXF 393 0.730 1.449 1.447 1.416 1.1780.057 0.060 100 95 62 −92 −92 1.20E−6 2.53E−6 5.33E−6 SN12C 0.737 2.5992.571 2.493 2.339 0.794 0.081 98 94 86 3 −89 2.72E−6 1.06E−5 3.77E−5TK-10 1.011 1.814 1.766 1.776 1.827 0.780 0.042 94 95 102 −23 −962.60E−6 6.55E−6 2.35E−5 UO-31 0.844 2.071 1.827 1.893 1.875 0.590 0.10580 86 84 −30 −88 1.99E−6 5.44E−6 2.22E−5 Prostate Cancer PC-3 0.6322.456 2.474 2.437 2.409 1.628 0.072 101 99 97 55 −89 1.08E−5 2.41E−55.38E−5 DU-145 0.442 1.803 1.825 1.796 1.618 0.410 −0.005 102 100 86 −7−100 2.44E−6 8.35E−6 2.89E−5 Breast Cancer MCF7 0.461 2.239 2.045 1.9351.736 0.313 0.117 89 83 72 −32 −75 1.62E−6 4.91E−6 2.64E−5 MDA-MB- 0.7691.644 1.651 1.578 1.464 0.634 0.123 101 92 79 −18 −84 2.01E−6 6.59E−63.07E−5 231/ATCC HS 578T 0.962 2.131 2049 2.851 2.000 1.652 0.861 93 9389 59 −10 1.35E−5 7.06E−5 >1.00E4   BT-549 0.866 1.956 1.951 1.934 1.8770.807 0.011 100 98 93 −7 −99 2.69E−6 8.54E−6 2.95E−5 T-47D 1.033 2.5972.492 2.352 2.373 1.229 0.564 93 84 86 13 −45 3.07E−6 1.64E−5 >1.00E4  MDA-MB- 0.768 1.381 1.307 1.357 0.986 0.397 0.191 88 96 36 −48 −755.78E−7 2.65E−6 1.15E−5 468

TABLE 12 NCI five dose result for JVM 2-70 Log10 Concentration Time MeanOptical Densities Percent Growth Panel/Cell Zero Ctrl −8.0 −7.0 −6.0−5.0 −4.0 −8.0 −7.0 −6.0 −5.0 −4.0 GI50 TGI LC50 Leukemia CCRF-CEM 0.4581.991 1.967 1.872 1.440 0.314 0.204 98 92 64 −32 −56 1.40E−6 4.68E−65.86E−5 HL-60(TB) 1.062 2.937 3.121 3.144 3.165 0.933 0.431 110 111 112−12 −59 3.16E−6 7.96E−6 6.31E−5 K-562 0.164 1.667 1.146 1.152 0.9810.229 0.103 109 109 90 7 −38 3.06E−6 1.45E−5 >1.00E−4  MOLT-4 0.7362.189 2.329 2.467 2.400 0.670 0.378 110 119 115 −9 −49 3.33E−68.45E−6 >1.00E−4  RPMI-8226 1.080 2.752 2.761 2.716 2.689 1.545 0.714101 98 96 28 −34 4.74E−6 2.82E−5 >1.00E−4  SR 0.462 1.777 1.789 1.8011.561 0.545 0.287 101 102 84 6 −38 2.72E−6 1.39E−5 >1.00E−4  Non-SmallCell Lung Cancer A549/ATCC 0.464 2.222 2.167 2.157 2.095 1.860 0.151 9796 93 79 −68 1.58E−5 3.47E−5 7.59E−5 HOP-62 0.764 2.343 2.129 2.2202.208 1.996 0.242 86 92 91 78 −68 1.55E−5 3.41E−5 7.49E−5 HOP-92 1.2611.952 1.860 1.832 1.754 1.281 0.109 87 83 71 3 −91 2.05E−6 1.07E−53.64E−5 NCI-H226 1.048 2.509 2.392 2.407 2.321 1.326 0.427 92 93 87 19−59 3.51E−6 1.75E−5 7.61E−5 NCI-H23 0.701 2.003 1.937 2.015 1.926 1.1290.213 95 101 94 33 −70 5.24E−6 2.09E−5 6.43E−5 NCI-H322M 0.835 1.9471.972 2.038 1.964 1.873 0.144 102 108 102 93 −83 1.76E−5 3.39E−5 6.51E−5NCI-H460 0.321 3.804 3.299 3.327 3.274 2.631 0.140 100 101 99 77 −571.60E−5 3.76E−5 8.94E−5 NCI-H522 1.088 2.503 2.409 2.444 2.214 0.1410.316 93 96 80 −87 −71 1.50E−6 3.00E−6 5.99E−6 Colon Cancer COLO 2050.512 1.898 1.813 1.990 1.951 0.456 0.059 94 107 104 −11 −88 2.94E−68.03E−6 3.19E−5 HCC-2998 0.753 2.198 2.283 2.246 2.339 1.599 0.153 106103 110 59 −80 1.15E−5 2.65E−5 6.10E−5 HCT-116 0.241 2.008 1.855 1.9141.631 0.129 0.018 91 95 79 −46 −93 1.69E−6 4.25E−6 1.19E−5 HCT-15 0.4202.691 2.468 2.462 2.096 0.298 0.127 90 91 74 −29 −70 1.70E−6 5.22E−63.26E−5 HT29 0.313 1.686 1.677 1.767 1.728 0.575 0.040 99 106 103 19 −874.28E−6 1.51E−5 4.45E−5 KM12 0.382 2.246 2.275 2.288 2.213 1.543 0.050102 102 98 62 −87 1.21E−5 2.61E−5 5.66E−5 SW-620 0.259 2.356 2.332 2.2901.911 0.270 0.053 99 97 79 1 −80 2.33E−6 1.02E−5 4.26E−5 CNS CancerSF-268 0.664 2.091 2.089 2.101 1.996 1.617 0.184 100 101 93 67 −721.32E−5 3.02E−5 6.91E−5 SF-295 0.791 2.940 2.695 2.791 2.789 2.387 0.22489 93 93 74 −72 1.47E−5 3.23E−5 7.10E−5 SF-539 1.057 2.915 2.762 2.8682.760 0.842 0.101 93 97 92 −20 −90 2.35E−6 6.58E−6 2.65E−5 SNB-19 0.7022.232 2.160 2.168 2.160 1.812 0.139 95 96 95 73 −80 1.40E−5 2.98E−56.34E−5 SNB-75 1.019 1.978 1.711 1.798 1.782 1.568 0.157 72 81 80 57 −851.12E−5 2.53E−5 5.70E−5 U251 0.618 2.355 2.270 2.263 2.336 2.186 0.05995 95 99 90 −90 1.67E−5 3.16E−5 5.97E−5 Melanoma LOX IMVI 0.548 2.7402.654 2.654 2.547 0.628 0.089 96 96 91 4 −84 2.95E−6 1.10E−5 4.10E−5MALME-3M 0.691 1.218 1.252 1.259 1.211 0.657 0.230 106 108 99 −5 −672.95E−6 8.96E−5 5.36E−5 M14 0.429 1.840 1.707 1.757 1.613 0.722 0.080 9194 84 21 −81 3.44E−6 1.60E−5 4.93E−5 MDA-MB- 0.580 2.847 2.592 2.7312.610 1.301 0.185 89 95 90 32 −72 4.84E−6 2.03E−5 6.19E−5 435 SK-MEL-20.921 1.582 1.622 1.661 1.633 1.368 0.165 106 112 108 68 −82 1.31E−52.83E−5 6.10E−5 SK-MEL-28 0.748 2.158 2.003 2.163 2.085 0.800 0.156 89100 95 4 −79 3.10E−6 1.11E−5 4.45E−5 8K-MEL-5 0.749 3.047 2.994 3.0252.949 1.721 0.049 98 99 96 42 −93 7.17E−6 2.05E−5 4.78E−5 UACC-257 0.9502.056 1.955 1.973 1.866 1.209 0.134 91 92 83 23 −86 3.57E−6 1.64E−54.70E−5 UACC-62 1.123 3.045 2.993 2.925 2.883 1.760 0.152 97 94 92 33−87 5.15E−6 1.89E−5 4.95E−5 Ovarian Cancer IGROVI 0.500 1.662 1.7711.874 1.709 0.721 0.241 109 118 104 19 −52 4.32E−6 1.85E−5 9.40E−5OVCAR-3 0.539 1.887 2.008 1.956 1.724 0.528 0.024 109 105 88 −2 −962.846-6 9.47E−6 3.25E−5 OVCAR-5 0.629 1.544 1.411 1.424 1.424 1.0040.067 86 87 87 41 −89 6.36E−6 2.06E−5 4.99E−5 OVCAR-8 0.553 2.249 2.1482.159 2.070 0.801 0.069 94 95 89 15 −88 3.37E−6 1.39E−5 4.29E−5 NCI/ADR-0.588 1.967 1.894 2.028 1.947 1.466 0.282 95 104 99 64 −52 1.31E−53.55E−5 9.60E−5 RES SK-OV-3 0.843 1.865 1.788 1.877 1856 1.811 0.762 92101 99 95 −10 2.68E−5 8.06E−5 >1.00E−4  Renal Cancer 786-0 0.595 2.4362.245 2.392 2.429 1.318 0.133 90 98 100 39 −78 6.64E−6 2.17E−5 5.80E−5A498 1.172 1.899 1.595 1.565 1.656 1.381 0.100 58 54 67 29 −92 2.77E−61.73E−5 4.52E−5 ACHN 0.458 2.029 1.995 2.057 1.797 0.488 0.095 98 102 852 −79 2.64E−6 1.05E−5 4.35E−5 CAKI-1 0.812 3.151 2.908 3.025 2.861 0.9170.057 90 95 88 4 −93 2.83E−6 1.11E−5 3.62E−5 RXF 393 0.730 1.435 1.4671.443 1.369 0.337 0.091 105 101 91 −54 −88 1.91E−6 4.24E−6 9.41E−6 SN12C0.737 2.753 2.684 2.604 2.602 1.344 0.133 97 93 92 30 −82 4.80E−61.86E−5 5.19E−5 TK-10 1.011 1.837 1.809 1.868 1.908 1.089 0.033 97 106109 9 −97 3.90E−6 1.23E−5 3.63E−5 UO-31 0.843 2.881 2.027 2.008 1.9371.077 0.138 96 94 88 19 −84 3.56E−6 1.53E−5 4.69E−5 Prostate Cancer PC-30.632 2.357 2.260 2.238 2.257 1.768 0.176 94 93 94 66 −72 1.30E−53.00E−5 6.91E−5 DU-145 0.442 1.829 1.928 1.908 1.757 0.797 0.051 107 10695 26 −89 4.44E−6 1.68E−5 4.59E−5 Breast Cancer MCF7 0.461 2.290 1.9732.075 1.817 0.543 0.171 83 88 74 4 −63 2.22E−6 1.16E−5 6.41E−5 MDA-MB-0.769 1.804 1.854 1.775 1.821 1.194 0.116 105 97 102 41 −85 7.13E−62.12E−5 5.28E−5 231/ATCC HS 578T 0.962 2.176 2.076 2.077 2.005 1.8091.034 92 92 86 70 6 2.04E−5 >1.00E−4  >1.00E−4  BT-549 0.866 1.731 1.5651.613 1.480 0.781 0.037 81 86 71 −10 −96 1.82E−6 7.55E−6 2.93E−5 T-47D1.033 2.668 2.432 2.575 2.564 1.596 0.536 86 94 94 34 −48 5.45E−62.61E−5 >1.00E−4  MDA-MB- 0.768 1.406 1.331 1.352 1.100 0.514 0.241 8892 52 −33 −69 1.06E−6 4.06E−6 2.98E−5 468

TABLE 13 NCI five dose result for JVM-57 Log10 Concentration Time MeanOptical Densities Percent Growth Panel/Cell Zero Ctrl −8.0 −7.0 −6.0−5.0 −4.0 −8.0 −7.0 −6.0 −5.0 −4.0 GI50 TGI LC50 Leukemia CCRF-CEM 0.6452.416 2.380 2.358 2.306 0.695 0.375 98 97 94 3 −42 3.03E−6 1.16E−51.09E−4 HL-60(TB) 0.952 3.038 3.038 3.062 2.926 1.248 0.430 100 101 9514 −55 3.59E−6 1.61E−5 8.51E−5 K-562 0.196 1.555 1.549 1.539 1.424 0.3850.164 100 99 90 14 −16 3.37E−6 2.88E−5 >1.00E−4  MOLT-4 0.598 2.1602.266 2.265 2.235 1.011 0.316 107 107 105 26 −47 5.00E−62.29E−5 >1.00E−4  RPMI-8226 1.212 2.701 2.704 2.657 2.684 1.724 0.638100 97 99 34 −47 5.72E−6 2.63E−5 >1.00E−4  SR 0.640 2.052 1.924 2.0731.873 0.936 0.438 91 101 87 21 −32 3.65E−6 2.51E−5 >1.00E−4  Non-SmallCell Lung Cancer A549/ATCC 0.383 1.974 1.844 1.890 1.896 1.817 0.414 9295 95 90 2 2.85E−5 >1.00E−4  >1.00E−4  HOP-62 0.694 1.596 1.658 1.6971.868 1.831 0.362 107 111 130 126 −48 2.74E−5 5.30E−5 >1.00E−4  HOP-921.344 1.817 1.130 1.834 1.731 1.268 0.140 82 104 82 −6 −90 2.30E−68.61E−6 3.37E−5 NCI-H226 1.086 1.864 1.734 1.772 1.727 1.671 1.361 83 8882 75 35 4.27E−5 >1.00E−4  >1.00E−4  NCI-H23 0.839 2.393 2.388 2.4512.443 2.042 0.234 100 104 103 77 −60 1.58E−5 3.65E−5 8.43E−5 NCI-H322M0.824 2.012 2.045 2.006 1.981 1.896 1.071 103 99 97 90 213.79E−5 >1.00E−4  >1.00E−4  NCI-H460 0.361 3.180 3.240 3.186 3.162 2.9750.340 102 100 99 93 −6 2.71E−5 8.73E−5 >1.00E−4  NCI-H522 0.699 1.8681.805 1.860 1.719 0.517 0.184 95 99 87 −26 −74 2.13E−6 5.88E−6 3.18E−5Colon Cancer COLO 205 0.601 3.020 3.085 3.071 3.157 1.738 0.202 103 102106 47 −66 8.89E−6 2.59E−5 7.16E−5 HCC-2998 0.936 3.069 3.126 3.1483.126 3.113 0.235 103 104 103 102 −75 1.97E−5 3.77E−5 7.23E−5 HCT-1160.214 1.663 1.681 1.662 1.517 0.254 0.029 101 100 98 3 −87 2.87E−61.07E−5 3.89E−5 HCT-15 0.373 2.246 2.232 2.135 2.139 1.345 0.206 99 9494 52 −45 1.05E−5 3.44E−5 >1.00E−4  HT29 0.298 1.591 1.622 1.693 1.7170.853 0.079 102 108 110 43 −74 7.83E−6 2.33E−5 6.27E−5 KM12 0.699 2.8862.933 3.012 2.883 2.784 0.612 102 106 100 95 −12 2.63E−57.66E−5 >1.00E−4  SW-620 0.304 1.945 1.919 1.918 1.885 0.082 0.109 98 9896 11 −64 3.48E−6 1.39E−5 6.48E−5 CNS Cancer SF-268 0.543 1.776 1.8181.779 1.798 1.466 0.112 103 100 102 75 −79 1.45E−5 3.05E−5 6.44E−5SF-295 0.971 2.941 2.887 2.852 2.916 2.904 1.956 97 95 99 9850 >1.00E−4  >1.00E−4  >1.00E−4  SF-539 1.018 2.786 2.669 2.699 2.7162.384 0.058 93 95 96 77 −94 1.44E−5 2.82E−5 5.52E−5 SNB-19 0.728 2.2742.227 2.195 2.175 2.084 1.196 97 95 94 88 30 4.53E−5 >1.00E−4  >1.00E−4 SNB-75 0.899 1.693 1.538 1.446 1.514 1.445 0.933 80 69 77 69 41.95E−5 >1.00E−4  >1.00E−4  U251 0.749 2.599 2.508 2.436 2.491 2.0601.217 95 91 94 92 25 4.29E−5 >1.00E−4  >1.00E−4  Melanoma LOX IMVI 0.3742.397 2.443 2.388 2.329 0.951 0.044 102 100 97 29 −88 4.84E−6 1.75E−54.70E−5 MALME-3M 0.712 1.292 1.292 1.243 1.277 0.928 0.202 100 91 97 37−72 6.12E−6 2.19E−5 6.32E−5 M14 0.497 1.783 1.782 1.805 1.735 1.0750.106 100 102 96 45 −79 7.97E−6 2.31E−5 5.85E−5 MDA-MB- 0.622 2.5522.485 2.527 2.519 1.308 0.199 97 99 98 36 −68 5.89E−6 2.20E−5 6.69E−5435 SK-MEL-2 0.987 2.000 2.125 2.158 2.113 1.668 0.234 112 116 111 67−76 1.32E−5 2.94E−5 6.55E−5 SK-MEL-28 0.500 1.560 1.498 1.482 1.4981.064 −0.008 94 93 94 53 −100 1.05E−5 2.22E−5 4.72E−5 8K-MEL-5 0.8362.755 2.582 2.655 2.592 2.125 0.012 91 95 91 67 −99 1.27E−5 2.54E−55.09E−5 UACC-62 0.981 2.982 3.004 2.862 2.667 2.202 0.079 101 94 94 61−92 1.18E−5 2.51E−5 5.32E−5 Ovarian Cancer IGROVI 0.521 1.390 1.4751.392 1.330 0.640 0.160 110 100 93 14 −69 3.49E−6 1.46E−5 5.86E−5OVCAR-3 0.855 2.267 2.385 2.391 2.278 1.373 0.019 109 109 101 37 −986.20E−6 1.87E−5 4.41E−5 OVCAR-4 0.622 1.454 1.424 1.407 1.344 1.0420.157 96 94 87 50 −75 1.01E−5 2.53E−5 6.34E−5 OVCAR-5 0.688 1.530 1.4971.540 1.441 1.347 0.241 95 101 89 78 −65 1.57E−5 3.52E−5 7.85E−5 OVCAR-80.526 2.247 2.246 2.248 2.203 1.577 0.279 100 100 97 61 −47 1.27E−53.68E−5 >1.00E−4  NCI/ADR- 0.735 2.260 2.305 2.349 2.343 2.225 1.213 103106 105 98 31 5.23E−5 >1.00E−4  >1.00E−4  RES SK-OV-3 0.731 2.189 2.2832.254 2.364 2.259 1.094 105 104 112 105 25 4.85E−5 >1.00E−4  >1.00E−4 Renal Cancer 786-0 0.831 2.694 2.780 2.797 2.737 1.909 0.153 105 106 10258 −82 1.14E−5 2.60E−5 5.94E−5 A498 1.638 2.554 2.470 2.457 2.397 2.3771.212 91 89 83 81 −26 1.94E−5 5.70E−5 >1.00E−4  ACHN 0.370 1.366 1.3831.389 1.325 0.529 0.052 102 102 96 16 −86 3.74E−6 1.43E−5 4.43E−5 CAKI-10.957 2.648 2.548 2.527 2.502 1.400 0.198 94 93 91 26 −79 4.31E−61.77E−5 5.27E−5 RXF 393 0.937 1.711 1.625 1.647 1.626 0.993 0.130 89 9289 7 −86 3.00E−6 1.19E−5 4.10E−5 SN12C 0.609 2.739 2.672 2.621 2.6522.299 0.441 97 94 96 79 −28 1.88E−5 5.52E−5 >1.00E−4  TK-10 0.710 1.3741.381 1.357 1.372 0.817 0.029 101 97 100 16 −96 3.93E−6 1.39E−5 3.89E−5UO-31 0.749 2.149 2.024 2.065 2.024 1.507 0.095 91 94 91 54 −87 1.07E−52.41E−5 5.45E−5 Prostate Cancer PC-3 0.575 2.086 2.021 2.012 2.030 1.7970.234 96 95 96 81 −59 1.66E−5 3.78E−5 8.58E−5 DU-145 0.418 1.688 1.7911.763 1.668 0.596 0.006 108 106 98 14 −99 3.74E−6 1.33E−5 3.70E−5 BreastCancer MCF7 0.260 1.688 1.630 1.535 1.601 0.060 0.067 96 89 94 14 −743.54E−6 1.44E−5 5.31E−5 MDA-MB- 0.760 1.921 1.982 1.898 1.916 1.5770.163 105 98 100 70 −79 1.37E−5 2.97E−5 6.43E−5 231/ATCC HS 578T 1.2092.350 2.253 2.244 2.238 1.982 1.313 91 91 90 68 92.01E−5 >1.00E−4  >1.00E−4  BT-549 0.984 2.075 2.108 2.064 2.073 1.2950.150 103 99 100 28 −85 4.99E−6 1.76E−5 4.93E−5 T-47D 0.661 1.157 1.8301.790 1.763 1.072 0.232 107 103 101 37 −65 6.32E−6 2.32E−5 7.15E−5MDA-MB- 0.972 2.079 1.933 1.948 1.953 1.120 0.304 87 88 89 13 −693.26E−6 1.46E−5 5.91E−5 468

TABLE 14 NCI five dose result for JVM-59 Log10 Concentration Time MeanOptical Densities Percent Growth Panel/Cell Zero Ctrl −8.0 −7.0 −6.0−5.0 −4.0 −8.0 −7.0 −6.0 −5.0 −4.0 GI50 TGI LC50 Leukemia CCRF-CEM 0.6452.318 2.250 2.275 2.069 0.622 0.252 96 97 85 −4 −61 2.49E−6 9.12E−66.43E−5 HL-60(TB) 0.952 3.120 2.860 3.030 3.005 1.437 0.352 88 96 95 22−63 4.15E−6 1.83E−5 7.03E−5 K-562 0.196 1.577 1.397 1.284 1.419 0.3810.125 87 79 89 13 −36 3.26E−6 1.86E−5 >1.00E−4  MOLT-4 0.598 2.259 2.2512.119 2.074 0.883 0.279 100 92 89 17 −53 3.48E−6 1.75E−5 8.97E−5RPMI-8226 1.212 2.598 2.650 2.574 2.551 1.864 0.591 184 98 97 47 −518.71E−6 3.01E−5 9.71E−5 SR 0.640 2.036 1.954 1.945 1.916 1.351 0.418 9493 91 51 −35 1.02E−5 3.93E−5 >1.00E−4  Non-Small Cell Lung CancerA549/ATCC 0.383 2.052 2.037 2.033 1.904 1.895 0.378 99 99 91 91 −12.76E−5 9.65E−5 >1.00E−4  HOP-62 0.694 1.533 1.436 1.438 1.458 1.9120.083 88 89 91 97 −88 1.80E−5 3.35E−5 6.23E−5 HOP-92 1.344 1.791 1.7091.713 1.713 1.215 0.148 82 83 83 −10 −89 2.25E−6 7.86E−6 3.23E−5NCI-H226 1.086 1.814 1.773 1.675 1.743 1.661 1.276 94 81 90 79 283.53E−5 >1.00E−4  >1.00E−4  NCI-H23 0.839 2.403 2.272 2.285 2.366 2.1090.305 92 92 96 81 −64 1.64E−5 3.63E−5 8.04E−5 NCI-H322M 0.824 1.9491.876 1.947 1.987 1.910 1.308 94 100 103 96 437.39E−5 >1.00E−4  >1.00E−4  NCI-H460 0.361 3.154 3.229 3.255 3.208 3.0970.217 103 104 102 98 −40 2.23E−5 5.14E−5 >1.00E−4  NCI-H522 0.699 1.8641.628 1.672 1.605 0.470 0234 80 83 76 −33 −67 1.78E−6 5.05E−6 3.22E−5Colon Cancer COLO 205 0.601 2.894 2.842 2.868 2.905 1.202 0.058 98 99100 26 −90 4.78E−6 1.68E−5 4.50E−5 HCC-2998 0.936 2.992 2.839 2.9343.147 3.030 0.181 93 97 106 102 −81 1.92E−5 3.61E−5 6.79E−5 HCT-1160.214 1.649 1.540 1.568 1.499 0.369 0.014 92 94 90 11 −94 3.18E−61.27E−5 3.82E−5 HCT-15 0.373 2.266 2.195 2.216 2.110 1.620 0.169 96 9792 66 −55 1.35E−5 3.51E−5 9.12E−5 HT29 0.298 1.592 1.562 1.601 1.5801.064 0.072 98 101 99 59 −76 1.17E−5 2.74E−5 6.44E−5 KM12 0.699 2.9632.866 2.851 2.920 2.745 0.584 96 95 96 90 −17 2.39E−5 7.00E−5 >1.00E−4 SW-620 0.304 1.845 1.827 1.832 1.738 0.509 0.059 99 99 93 13 −81 3.46E−61.38E−5 4.72E−5 CNS Cancer SF-268 0.543 1.788 1.731 1.767 1.758 1.5070.081 95 98 96 77 −85 1.47E−5 3.00E−5 6.08E−5 SF-295 0.971 2.968 2.8842.877 2.893 2.804 1.592 96 95 96 92 31 4.88E−5 >1.00E−4  >1.00E−4 SF-539 1.018 2.680 2.628 2.612 2.652 2.372 0.022 97 96 96 81 −98 1.50E−52.85E−5 5.41E−5 SNB-19 0.728 2.112 2.090 1.992 2.082 1.934 1.268 98 9196 87 39 5.91E−5 >1.00E−4  >1.00E−4  SNB-75 0.899 1.697 1.541 1.6381.557 1.456 0.829 80 93 82 70 −8 1.80E−5 7.93E−5 >1.00E−4  U251 0.7492.696 2.617 2.600 2.587 2.487 0.728 96 95 94 89 −3 2.67E−59.31E−5 >1.00E−4  Melanoma LOX IMVI 0.374 2.424 2.317 2.281 2.345 1.2900.089 95 93 96 45 −76 7.88E−6 2.34E−5 6.06E−5 MALME-3M 0.712 1.262 1.2121.224 1.271 0.814 0.187 91 93 102 18 −74 4.18E−6 1.59E−5 5.52E−5 M140.497 1.786 1.707 1.684 1.655 1.134 0.096 94 92 90 49 −81 9.65E−62.40E−5  581E−5 MDA-MB- 0.622 2.459 2.472 2.446 2.352 1.358 0.102 101 9994 40 −84 6.56E−6 2.11E−5 5.34E−5 435 SK-MEL-2 0.688 1.978 1.968 1.9612.027 1.703 0.163 99 96 105 72 −81 1.40E−5 2.95E−5 6.24E−5 SK-MEL-280.526 1.553 1.545 1.596 1.544 1.177 0.023 99 104 99 64 −95 1.23E−52.53E−5 5.20E−5 8K-MEL-5 0.735 2.634 2.605 2.501 2.552 2.352 0.027 98 9395 84 −97 1.55E−5 2.92E−5 5.51E−5 UACC-62 0.731 2.836 2.786 2.826 2.7232.280 0.092 97 99 94 70 −91 1.33E−5 2.73E−5 5.58E−5 Ovarian CancerIGROVI 0.521 1.353 1.406 1.328 1.372 0.661 0.192 106 97 102 17 −634.09E−6 1.62E−5 6.85E−5 OVCAR-3 0.855 2.276 2.289 2.278 2.310 1.5050.018 101 100 102 46 −98 8.41E−6 2.08E−5 4.64E−5 OVCAR-4 0.622 1.4181.361 1.360 1.323 1.039 0.118 93 93 BB 52 −81 1.04E−5 2.47E−5 5.85E−5OVCAR-5 0.688 1.495 1.443 1.461 1.406 1.254 0.102 94 9B 89 70 −85 135E−5 2.83E−5 5.93E−5 OVCAR-8 0.526 2.277 2.222 2.164 2.232 1.7060.162 97 94 97 67 −69 1.34E−5 3.11E−5 7.22E−5 NCI/ADR- 0.735 2.289 2.2812.284 2.327 2.211 1.547 99 100 102 95 52 >1.00E−4  >1.00E−4  >1.00E−4 RES SK-OV-3 0.731 2.137 2.089 2.086 2.129 1.950 0.849 97 96 99 87 82.94E−5 >1.00E−4  >1.00E−4  Renal Cancer 786-0 0.831 2.600 2.531 2.5242.489 2.170 0.118 96 96 34 76 −86 1.44E−5 2.94E−5 6.00E−5 A498 1.6382.499 2.513 2.415 2.393 2.468 0.767 102 96 88 96 −53 2.04E−5 4.41E−59.52E−5 ACHN 0.370 1.318 1.342 1.300 1.244 0.555 0.011 103 98 92 19 −973.80E−6 1.47E−5 3.94E−5 CAKI-1 0.957 2.615 2.534 2.526 2.460 1.654 0.12795 95 91 42 −87 6.86E−6 2.12E−5 5.18E−5 RXF 393 0.937 1.669 1.603 1.5751.593 1.118 0.140 91 87 90 25 −85 4.08E−6 1.68E−5 4.79E−5 SN12C 0.6092.537 2.539 2.494 2.528 2.276 0.244 100 98 100 86 −60 1.77E−5 3.90E−58.55E−5 TK-10 0.710 1.455 1.404 1.344 1.324 0.834 0.046 93 85 82 17 −943.11E−6 1.41E−5 4.02E−5 UO-31 0.749 2.101 1.890 1.938 2.001 1.656 0.25164 88 93 67 −66 1.34E−5 3.18E−5 7.53E−5 Prostate Cancer PC-3 0.575 2.1802.050 2.077 2.029 1.862 0.151 92 94 91 80 −74 1.57E−5 3.32E−5 7.01E−5DU-145 0.418 1.693 1.702 1.698 1.715 0.958 0.015 101 100 102 42 −967.42E−6 2.02E−5 4.63E−5 Breast Cancer MCF7 0.260 1.695 1.625 1.662 1.5960.551 0.086 95 98 93 20 −67 3.91E−6 1.71E−5 6.37E−5 MDA-MB- 0.760 1.7691.824 1.810 1.821 1.569 0.117 105 104 105 80 −85 1.52E−5 3.06E−5 6.16E−5231/ATCC HS 578T 1.209 2.247 2.190 2.207 2.221 2.010 1.030 94 96 97 77−15 1.97E−5 6.90E−5 >1.00E−4  BT-549 0.984 2.061 1.928 2.004 1.932 1.3270.065 88 95 88 32 −93 4.75E−6 1.86E−5 4.50E−5 T-47D 0.661 1.609 1.5811.567 1.607 0.919 0.207 97 96 100 27 −69 4.86E−6 1.92E−5 6.38E−5 MDA-MB-0.972 1.955 1.906 1.802 1.762 0.937 0.224 95 84 80 −4 −77 2.30E−69.06E−6 4.29E−5 468

TABLE 15 NCI five dose result for JVM-61 Log10 Concentration Time MeanOptical Densities Percent Growth Panel/Cell Zero Ctrl −8.0 −7.0 −6.0−5.0 −4.0 −8.0 −7.0 −6.0 −5.0 −4.0 GI50 TGI LC50 Leukemia CCRF-CEM 0.6662.444 2.510 2.441 2.290 0.623 0.407 104 100 91 −6 −39 2.65E−68.59E−6 >1.00E−4  MOLT-4 0.920 2.884 3.000 3.009 2.987 1.528 0.483 106106 105 31 −47 5.54E−6 2.50E−5 >1.00E−4  RPMI-8226 1.575 3.067 3.1003.071 3.063 2.251 1.076 102 100 100 45 −32 8.20E−6 3.88E−5 >1.00E−4  SR0.811 2.566 2.547 2.574 2.472 1.193 0.536 99 100 95 22 −34 4.10E−62.46E−5 >1.00E−4  Non-Small Cell Lung Cancer A549/ATCC 0.365 2.018 1.9391.516 1.605 1.419 0.167 95 BB 6.7 64 −54 1.31E−5 3.47E−5 9.20E−5 HOP-620.645 1.658 1.649 1.682 1.739 1.571 0.223 99 102 108 91 −65 1.84E−53.83E−5 7.97E−5 HOP-92 1.575 1.975 1.903 1.549 1.555 1.622 0.206 0.2 6671 12 −87 2.25E−6 1.31E−5 4.22E−5 NCI-H226 0.811 1.837 1.778 1.756 1.7471.525 0.310 94 92 91 70 −62 1.41E−5 3.38E−5 8.13E−5 NCI-H23 0.686 1.9942.042 2.010 1.993 1.424 0.259 104 101 100 56 −62 1.13E−5 2.99E−5 7.88E−5NCI-H322M 0.723 1.947 2.025 1.988 2.003 1.789 0.593 106 103 105 87 −182.25E−5 6.34E−5 >1.00E4   NCI-H460 0.285 2.805 2.914 2.640. 2.865 2.0280.139 104 102 102 69 −51 1.44E−5 3.75E−5 9.74E−5 NCI-H522 0.880 2.2622.190 2.211 1.963 0.403 0.270 95 96 76 −54 −69 1.64E−6 3.90E−6 9.29E−6Colon Cancer COLO 205 0.583 2.505 2.579 2.668 2.624 0.649 0.124 104 108107 3 −79 3.54E−6 1.10E−5 4.46E−5 HCC-2998 1.076 2.956 2.970 3.015 2.9602.703 0.154 101 103 100 87 −86 1.63E−5 3.18E−5 6.21E−5 HCT-116 0.2121.571 1.557 1.600 1.325 0.141 0.003 99 102 82 −33 −99 1.59E−6 5.12E−61.79E−5 HCT-15 0.465 2.478 2.439 2.424 2.249 0.908 0.089 98 97 89 22 −813.50E−6 1.54E−5 5.01E−5 HT29 0.315 1.704 1.761 1.786 1.843 0.649 0.069104 106 110 24 −78 4.69E−6 1.72E−5 5.31E−5 KM12 0.586 2.507 2.609 2.6372.566 2.274 0.084 105 107 103 88 −86 1.65E−5 3.21E−5 6.22E−5 SW-6200.308 1.873 2.017 1.954 1.752 0.419 0.091 109 105 92 7 −70 3.13E5 1.23E−5 5.45E−5 CNS Cancer SF-268 0.720 2.227 2.323 2.362 2.263 1.9590.199 106 109 102 82 −72 1.62E−5 3.40E−5 7.17E−5 SF-539 0.810 2.4612.461 2.410 2.395 1.398 0.008 103 97 96 36 −99 5.77E−6 1.54E−5 4.32E−5SNB-19 0.798 2.328 2.278 2.215 2.234 2.137 0.839 97 93 94 88 3 2.77E−51.60E−4 >1.00E4   SNB-75 0.999 1.780 1.634 1.596 1.576 1.252 0.121 81 7674 32 −88 3.78E−6 1.86E−5 4.84E−5 U251 0.400 1.987 1.939 1.850 1.8701.434 0.043 97 91 93 65 −89 1.25E−5 2.54E−5 5.56E−5 Melanoma LOX IMVI0.459 2.550 2.531 2.602 2.457 1.087 0.117 99 102 96 30 −75 4.96E−61.94E−5 5.82E−5 MALME-3M 0.661 1.307 1.395 1.305 1.276 0.943 0.283 114100 95 44 −57 7.52E−6 2.71E−5 8.49E−5 M14 0.496 1.572 1.568 1.597 1.5380.863 0.159 100 102 97 34 −68 5.58E−6 2.16E−5 6.67E−5 MDA-MB- 0.5482.381 2.328 2.271 2.265 1.237 0.230 97 94 94 38 −58 6.01E−6 2.47E−58.24E−5 435 SK-MEL-2 1.320 2.305 2.397 2.403 2.426 2.079 0.338 109 110112 77 −74 1.51E−5 3.23E−5 6.90E−5 SK-MEL-28 0.490 1.475 1.517 1.4511.435 0.807 0.036 104 96 96 32 −93 5.25E−6 1.81E−5 4.55E−5 8K-MEL-50.753 2.896 2.815 2.783 2.819 1.815 0.042 96 95 96 50 −94 9.78E−62.21E−5 4.91E−5 UACC-257 0.666 1.567 1.538 1.494 1.415 0.964 0.128 97 9283 33 −81 4.59E−6 1.95E−5 5.37E−5 UACC-62 0.896 2.579 2.586 2.449 2.3921.573 0.086 100 92 89 40 −90 6.29E−6 2.03E−5 4.90E−5 Ovarian CancerIGROVI 0.747 2.434 2.528 2.505 2.465 1.955 0.270 106 104 102 72 −641.44E−5 3.38E−5 7.89E−5 OVCAR-4 0.782 1.404 1.425 1.379 1.400 1.0410.274 103 96 99 42 −65 7.17E−6 2.46E−5 7.23E−5 OVCAR-5 0.650 1.521 1.5811.4913 1.485 1.096 0.036 107 97 96 51 −94 1.02E−5 2.25E−5 4.95E−5OVCAR-8 0.330 1.507 1.603 1.504 1.454 0.620 0.109 108 100 96 25 −674.39E−6 1.85E−5 6.51E−5 NCI/ADR- 0.644 2.153 2.231 2.242 2.251 1.9260.450 105 106 106 85 −30 2.01E−5 5.47E−5 >1.00E−4  RES SK-OV-3 0.7922.022 2.099 2.109 2.060 1.857 0.784 106 187 103 87 −1 2.62E−59.74E−5 >1.00E−4  Renal Cancer 786-0 0.594 2.319 2.345 2.329 2.252 0.8530.040 101 101 96 15 −93 3.70E−6 1.38E−5 3.98E−5 A498 1.515 2.009 1.9461.920 1.945 1.788 0.044 87 B2 87 55 −97 1.68E−5 2.51E−5 4.91E−5 ACHN0.388 1.552 1.574 1.520 1.377 0.450 0.010 102 97 85 5 −98 2.75E−61.13E−5 3.45E−5 CAKI-1 0.668 2.591 2.571 2.446 2.351 0.783 0.116 99 9388 6 −83 2.88E−6 1.17E−5 4.28E−5 RXF 393 0.880 1.652 1.659 1.569 1.4640.892 0.199 101 B9 76 2 −77 2.22E−6 1.55E−5 4.50E−5 SN12C 0.631 2.3022.219 2.172 2.151 1.317 0.191 95 92 91 41 −70 6.61E−6 2.54E−5 6.63E−5TK-10 0.733 1.539 1.543 1.573 1.553 0.831 0.029 101 104 102 12 −963.13E−6 1.29E−5 3.75E−5 UO-31 0.739 2.172 2.069 2.073 2.016 1.319 0.09793 93 89 40 −87 6.38E−6 2.08E−5 5.13E−5 Prostate Cancer PC-3 0.749 2.8432.805 2.742 2.775 2.491 0.245 98 95 97 83 −67 1.56E−5 3.57E−5 7.68E−5DU-145 0.436 1.926 1.953 2.043 1.886 0.820 0.057 102 108 97 26 −874.59E−6 1.69E−5 4.70E−5 Breast Cancer MCF7 0.290 1.706 1.581 1.54131.459 0.409 0.100 91 B9 85 8 −66 2.65E−6 1.30E−5 6.14E−5 MDA-MB- 0.8422.028 2.062 2.029 1.976 1.533 0.120 103 100 96 58 −86 1.14E−5 2.54E−55.64E−5 231/ATCC HS 578T 0.902 1.883 1.868 1.1367 1.823 1.179 0.677 9896 94 28 −25 4.66E−6 3.39E−5 1.00E−4 BT-549 0.876 1.824 1.789 1.7571.653 0.880 0.042 96 96 85 . −95 2.60E−6 1.01E−5 3.36E−5 T-47D 0.5721.338 1.319 1.370 1.385 0.842 0.324 98 104 106 35 −43 6.19E−62.50E−5 >1.00E−4  MDA-MB- 0.884 2.026 1.964 1.898 1.831 1.091 0.301 9589 83 18 −66 3.22E−6 1.64E−5 6.45E−5 468

TABLE 16 NCI five dose result for JVM-64 Log10 Concentration Time MeanOptical Densities Percent Growth Panel/Cell Zero Ctrl −8.0 −7.0 −6.0−5.0 −4.0 −8.0 −7.0 −6.0 −5.0 −4.0 GI50 TGI LC50 Leukemia CCRF-CEM 0.6662.500 2.526 2.398 1.375 0.457 0.291 101 94 39 −31 −56 6.26E−7 3.56E−65.58E−5 MOLT-4 0.920 2.854 2.936 2.974 2.666 0.736 0.445 104 106 90 −20−52 2.32E−6 6.59E−6 8.85E−5 RPMI-8226 1.575 3.083 3.099 3.081 2.9701.398 0.858 101 100 93 −11 −46 2.57E−6 7.79E−6 >1.00E−4  SR 0.811 2.5522.524 2.598 2.354 0.888 0.408 98 103 139 −15 −50 2.36E−67.13E−6 >1.00E−4  Non-Small Cell Lung Cancer A549/ATCC 0.365 1.890 1.8601.836 1.781 0.731 0.160 98 96 93 24 −56 4.19E−6 1.99E−5 8.35E−5 HOP-620.645 1.593 1.694 1.655 1.616 1.002 0.192 111 106 102 38 −70 6.45E−62.23E−5 6.49E−5 HOP-92 1.575 1.951 1.878 1.855 1.749 1.072 0.157 78 7245 −32 −90 6.55E−7 3.84E−6 2.04E−5 NCI-H226 0.811 1.836 1.714 1.7081.734 1.332 0.405 88 88 90 51 −50 1.02E−5 3.19E−5 9.97E−5 NCI-H23 0.6862.050 2.123 2.098 1.917 0.833 0.262 105 103 90 11 −62 3.21E−6 1.41E−56.36E−5 NCI-H322M 0.723 1.869 1.833 1.919 1.844 1.571 0.109 97 104 98 74−85 1.42E−5 2.92E−5 6.03E−5 NCI-H460 0.285 2.898 2.935 2.865 2.852 0.7690.148 101 99 98 19 −48 4.03E−6 1.89E−5 >1.00E−4  NCI-H522 0.880 2.2252.162 2.179 1.724 0.332 0.294 95 97 63 −62 −67 1.26E−6 3.17E−6 7.87E−6Colon Cancer COLO 205 0.583 2.416 2.551 2.626 2.261 0.164 0.110 107 11192 −72 −81 1.79E−6 3.63E−6 7.35E−6 HCC-2998 1.076 3.147 3.158 3.1783.230 1.962 0.153 101 102 104 43 −86 7.63E−6 2.15E−5 5.27E−5 HCT-1160.212 1.614 1.629 1.580 1.018 0.040 0.014 101 98 57 −81 −94 1.13E−62.60E−6 5.86E−6 HCT-15 0.465 2.447 2.448 2.336 2.107 0.448 0.077 100 94133 −4 −84 2.40E−6 9.05E−6 3.80E−5 HT29 0.315 1.663 1.695 1.678 1.5530.280 0.067 102 101 92 −11 −79 2.55E−6 7.77E−6 3.74E−5 KM12 0.586 2.5032.577 2.653 2.518 0.906 0.052 104 108 101 17 −91 4.01E−6 1.43E−5 4.15E−5SW-620 0.308 1.978 1.960 1.955 1.239 0.129 0.077 99 99 56 −58 −751.12E−6 3.09E−6 8.49E−6 CNS Cancer SF-268 0.720 2.295 2.331 2.313 2.2430.958 0.179 102 101 97 15 −75 3.73E−6 1.47E−5 5.26E−5 SF-295 1.051 3.0462.977 2.959 3.015 2.502 0.217 97 96 98 73 −79 1.41E−5 3.01E−5 6.41E−5SF-539 0.810 2.472 2.409 2.334 2.203 0.378 0.029 96 92 84 −53 −961.76E−6 4.08E−6 9.46E−6 SNB-19 0.798 2.287 2.214 2.147 2.173 1.919 0.40295 91 92 75 −50 1.59E−5 4.00E−5 >1.00E−4  SNB-75 0.999 1.704 1.582 1.5341.458 1.002 0.041 83 76 65 . −96 1.71E−6 1.01E−5 3.34E−5 U251 0.4001.952 1.919 1.820 1.773 0.705 0.085 98 92 68 20 −79 3.62E−6 1.58E−55.10E−5 Melanoma LOX IMVI 0.459 2.674 2.831 2.697 2.346 0.293 0.081 98101 B5 −36 −82 1.95E−6 5.03E−6 1.98E−5 MALME-3M 0.661 1.276 1.302 1.2671.189 0.582 0.302 104 99 66 −12 −54 2.32E−6 7.53E−6 7.88E−5 M14 0.4961.511 1.468 1.463 1.320 0.134 0.012 96 95 81 −73 −98 1.59E−6 3.36E−67.09E−6 MDA-MB- 0.548 2.425 2.361 2.414 2.140 0.468 0.246 97 99 65 −15−55 2.24E−6 7.13E−6 7.48E−5 435 SK-MEL-2 1.320 2.638 2.877 2.662 2.6501.434 0.459 103 103 101 9 −65 3.56E−6 1.31E−5 6.22E−5 SK-MEL-28 0.4901.498 1.500 1.461 1.315 0.308 0.061 100 96 82 −37 −88 1.85E−6 4.86E−61.79E−5 8K-MEL-5 0.753 2.989 2.856 2.829 2.761 0.967 0.044 94 93 90 10−94 3.13E−6 1.24E−5 3.75E−5 UACC-257 0.666 1.485 1.499 1.424 1.237 0.5350.135 102 93 70 −20 −80 1.66E−6 6.02E−6 3.19E−5 UACC-62 0.896 2.6292.567 2.521 2.171 0.523 0.097 96 94 74 −42 −89 1.60E−6 4.35E−6 1.50E−5Ovarian Cancer IGROVI 0.747 2.293 2.380 2.378 2.268 0.941 0.228 106 10598 13 −70 3.66E−6 1.42E−5 5.78E−5 OVCAR-4 0.782 1.364 1.300 1.302 1.2090.946 0.234 89 89 73 28 −70 3.28E−6 1.93E−5 6.24E−5 OVCAR-5 0.650 1.5711.546 1.498 1.471 0.479 0.073 97 92 69 −26 −89 2.18E−6 5.92E−6 2.40E−5OVCAR-8 0.330 1.484 1.526 1.478 1.290 0.405 0.090 104 99 83 6 −732.71E−6 1.21E−5 5.16E−5 NCI/ADR- 0.644 2.189 2.231 2.281 2.260 1.8330.771 103 106 105 77 8 2.47E−5 >1.00E−4  >1.00E−4  RES SK-OV-3 0.7922.032 2.024 2.111 2.068 1.498 0.429 99 106 103 57 −46 1.17E−53.58E−5 >1.00E−4  Renal Cancer 786-0 0.594 2.278 2.249 2.282 2.016 0.1640.040 98 100 84 −72 −93 1.66E−6 3.45E−6 7.20E−6 A498 1.515 2.035 2.0151.976 1.997 1.333 0.037 96 89 93 −12 −98 2.56E−6 7.67E−6 2.78E−5 ACHN0.388 1.506 1.527 1.485 1.254 0.253 0.020 102 98 77 −35 −95 1.75E−64.89E−6 1.78E−5 CAKI-1 0.668 2.539 2.484 2.515 2.121 0.570 0.152 97 9978 −15 −77 1.99E−6 6.93E−6 3.66E−5 RXF 393 0.880 1.618 1.586 1.557 1.2350.196 0.209 96 92 48 −78 −76 9.06E−7 2.41E−6 6.02E−6 SN12C 0.631 2.4092.206 2.267 2.252 0.871 0.138 89 92 91 2 −78 2.90E−6 1.07E−5 4.46E−5TK-10 0.733 1.555 1.606 1.581 1.507 0.616 0.047 106 103 94 −16 −942.51E−6 7.16E−6 2.74E−5 UO-31 0.739 2.161 2.021 1.997 1.831 0.638 0.13390 88 77 −14 −82 1.98E−6 7.86E−6 3.40E−5 Prostate Cancer PC-3 0.7492.760 2.719 2.705 2.652 1.687 0.282 98 97 95 47 −62 8.51E−6 2.68E−57.70E−5 DU-145 0.436 1.844 1.958 1.954 1.757 0.622 0.003 108 108 94 13−99 3.49E−6 1.31E−5 3.84E−5 Breast Cancer MCF7 0.290 1.740 1.598 1.5801.117 0.308 0.118 90 89 57 1 −59 1.33E−6 1.05E−5 7.02E−5 MDA-MB- 0.8422.090 2.125 2.099 2.050 0.812 0.133 103 101 97 −4 −84 2.93E−6 9.22E−63.77E−5 231/ATCC HS 578T 0.902 1.910 1.824 1.834 1.759 0.855 0.651 91 9265 −5 −28 2.44E−6 8.75E−6 >1.00E−4  BT-549 0.876 1.792 1.749 1.732 1.5780.153 0.038 95 93 77 −83 −96 1.47E−6 3.83E−6 6.24E−6 T-47D 0.572 1.2911.318 1.324 1.265 0.363 0.273 104 104 96 −37 −52 2.23E−6 5.31E−6 7.09E−5MDA-MB- 0.884 1.989 1.958 1.860 1.562 0.533 0.265 97 88 61 −40 −701.29E−6 4.04E−6 2.18E−5 468

TABLE 17 NCI five dose result for JVM-66 Log10 Concentration Time MeanOptical Densities Percent Growth Panel/Cell Zero Ctrl −8.0 −7.0 −6.0−5.0 −4.0 −8.0 −7.0 −6.0 −5.0 −4.0 GI50 TGI LC50 Leukemia CCRF-CEM 0.6452.380 2.374 2.367 2.258 0.847 0.379 100 99 93 12 −41 3.38E−61.66E−5 >1.00E−4 HL-60(TB) 0.952 3.162 3.062 3.177 3.264 1.315 0.358 95101 102 16 −62 4.05E−6 1.62E−5  6.95E−5 K-562 0.196 1.508 1.455 1.3751.509 0.400 0.212 96 90 100 16 1 1.91E−5 >1.00E−4  >1.00E−4 MOLT-4 0.5982.301 2.286 2.336 2.307 1.242 0.403 99 102 100 38 −33 6.38E−63.44E−5 >1.00E−4 RPMI-8226 1.212 2.660 2.706 2.710 2.694 1.986 0.836 103103 102 53 −31 1.10E−5 4.29E−5 >1.00E−4 SR 0.640 2.155 2.105 2.089 2.1271.204 0.471 97 96 98 37 −26 6.17E−6 3.85E−5 >1.00E−4 Non-Small Cell LungCancer A549/ATCC 0.383 1.943 1.967 1.937 1.839 1.761 0.476 102 100 93 886 19.2E−5 1.06E−4 >1.00E−4 HOP-62 0.694 1.587 1.564 1.555 1.692 1.8090.636 97 96 112 125 −8 3.65E−5 8.656-5 >1.00E−4 HOP-92 1.344 1.864 1.8181.779 1.769 1.571 0.563 31 84 82 44 −58 6.83E−6 2.69E−5  8.32E−5NCI-H226 1.086 1.054 1.806 1.685 1.799 1.683 1.470 94 78 93 78 509.96E−5 >1.00E−4  >1.00E−4 NCI-H23 0.839 2.355 2.245 2.304 2.364 1.9410.664 93 97 101 73 −21 1.35E−5 5.98E−5 >1.00E−4 NCI-H322M 0.824 2.1192.037 2.021 2.118 2.074 1.359 94 92 100 96 41 6.95E−5 1.06E−4 >1.00E−4NCI-H460 0.361 3.179 3.255 3.307 3.251 3.071 0.302 103 105 103 96 −161.57E−5 7.14E−5 >1.00E−4 NCI-H522 0.699 1.837 1.705 1.690 1.751 1.0760.227 88 87 92 33 −68 5.19E−6 2.13E−5  6.69E−5 Colon Cancer COLO 2050.601 3.035 2.919 2.947 3.032 2.127 0.123 95 96 100 63 −80 1.23E−52.76E−5  6.19E−5 HCC-2998 0.936 3.032 3.027 3.012 3.122 2.808 0.144 10099 104 89 −85 1.68E−5 1.26E−5  6.32E−5 HCT-116 0.214 1.714 1.661 1.6281.613 0.178 0.041 96 94 93 −17 −81 2.47E−6 7.03E−6  3.30E−5 HCT-15 0.3732.202 2.082 2.103 2.042 1.141 0.169 93 95 91 42 −55 6.88E−6 2.71E−5 8.92E−5 HT29 0.298 1.590 1.571 1.596 1.656 1.078 0.089 99 100 105 60−70 1.20E−5 2.90E−5  6.99E−5 KM12 0.699 2.840 2.849 2.138 2.813 2.8161.973 100 102 99 99 60 >1.00E−4  >1.00E−4  >1.00E−4 SW-620 0.304 1.9601.917 1.948 1.855 0.803 0.123 97 99 94 30 −60 4.86E−6 2.17E−5  7.83E−5CNS Cancer SF-268 0.543 1.807 1.753 1.795 1.779 1.615 0.449 96 99 98 85−17 2.19E−5 6.77E−5 >1.00E−4 SF-295 0.971 2.971 2.838 2.659 2.860 2.7941.534 93 94 94 91 28 4.50E−5 1.06E−4 >1.00E−4 SF-539 1.018 2.698 2.6272.615 2.638 2.465 0.244 96 95 96 86 −76 1.67E−5 3.40E−5  6.91E−5 SNB-190.728 2.299 2.188 2.199 2.180 2.029 1.327 93 94 92 83 385.43E−5 >1.00E−4  >1.00E−4 SNB-75 0.899 1.846 1.651 1.692 1.695 1.5861.228 79 84 84 72 35 3.93E−5 >1.06E−4  >1.00E−4 U251 0.749 2.605 2.5682.535 2.524 2.487 0.906 98 96 96 94 8 3.25E−5 >1.00E−4  >1.00E−4Melanoma LOX IMVI 0.374 2.319 2.266 2.187 2.229 0.498 0.066 97 93 95 6−82 3.23E−6 1.18E−5  4.31E−5 MALME-3M 0.712 1.324 1.290 1.291 1.3681.115 0.487 94 95 107 66 −32 1.45E−5 4.74E−5 >1.00E−4 M14 0.497 1.8451.764 1.762 1.733 1.332 0.220 94 94 92 62 −56 1.26E−5 3.36E−5  8.92E−5MDA-MB- 0.622 2.670 2.569 2.617 2.503 2.191 0.356 95 97 92 77 −431.67E−5 4.38E−5 >1.00E−4 435 SK-MEL-2 0.987 1.974 2.002 1.953 1.9691.760 0.452 103 96 99 78 −54 1.64E−5 3.96E−5  9.30E−5 SK-MEL-28 0.5001.654 1.655 1.725 1.581 1.359 0.248 100 136 94 74 −50 1.57E−5 3.95E−5 9.93E−5 8K-MEL-5 0.836 2.736 2.680 2.494 2.590 2.221 0.067 97 87 92 73−92 1.33E−5 2.77E−5  5.56E−5 UACC-62 0.981 2.984 2.896 2.861 2.849 2.3770.321 96 94 93 70 −67 1.39E−5 3.23E−5  7.48E−5 Ovarian Cancer IGROVI0.521 1.514 1.570 1.518 1.521 0.995 0.310 106 100 161 48 −41 9.04E−6 347E−5 >1.00E−4 OVCAR-3 0.855 2.245 2.264 2.247 2.294 1.587 0.037 101130 103 53 −96 1.04E−5  /26E−5  4.92E−5 OVCAR-4 0.622 1.513 1.470 1.4331.421 1.267 0.603 95 91 90 72 −3 1.98E−5 9.09E−5 >1.00E−4 OVCAR-5 0.6881.525 1.474 1.475 1.509 1.420 0.230 94 94 98 88 −67 1.35E−5  176E−5 7.81E−5 OVCAR-8 0.526 2.297 2.236 2.278 2.263 1.843 0.535 97 99 98 74 11.14E−5 >1.00E−4  >1.00E−4 NCI/ADR- 0.735 2.272 2.201 1.201 2.264 2.0420.916 95 95 96 85 12 3.01E−5 >1.00E−4  >1.00E−4 RES SK-OV-3 0.731 2.1812.161 2.184 2.242 2.112 1.279 99 100 104 95 386.14E−5 >1.00E−4  >1.00E−4 Renal Cancer 786-0 0.831 2.755 2.674 2.6892.718 2.407 0.337 96 97 98 82 −60 1.68E−5 3.79E−5  8.57E−5 A498 1.6382.518 2.499 2.445 2.489 2.479 1.286 98 92 97 95 −21 1.45E−56.55E−5 >1.00E−4 ACHN 0.370 1.340 1.293 1.255 1.370 0.748 0.048 95 91103 39 −87 6.73E−6 2.04E−5  5.07E−5 CAKI-1 0.957 2.801 2.726 2.743 2.7572.119 0.315 96 97 98 63 −67 1.26E−5 3.05E−5  7.38E−5 RXF 393 0.937 1.7501.725 1.663 1.700 0.970 0.308 97 82 94 4 −67 3.08E−6 1.14E−5  5.74E−5SN12C 0.609 2.738 2.703 2.743 2.627 2.441 0.243 98 100 95 86 −60 1.37E−51.88E−5  8.53E−5 TK-10 0.710 1.422 1.350 1.363 1.359 1.088 0.131 90 9291 53 −82 1.05E−5 2.48E−5  5.82E−5 UO-31 0.749 2.204 1.951 1.998 2.0501.429 0.151 83 86 89 47 −80 8.37E−6 2.34E−5  5.81E−5 Prostate CancerPC-3 0.575 2.155 2.155 2.072 2.089 1.926 0.470 100 95 96 85 −18 1.20E−56.66E−5 >1.00E−4 DU-145 0.418 1.705 1.722 1.679 1.715 1.223 0.070 101 98161 63 −83 1.22E−5 2.69E−5  5.91E−5 Breast Cancer MCF7 0.260 1.848 1.7941.832 1.700 0.662 0.105 97 99 91 25 −60 4.19E−6 1.98E−5  7.67E−5 MDA-MB-0.760 1.877 1.947 1.880 1.849 1.646 0.245 106 100 97 79 −68 1.58E−53.46E−5  7.57E−5 231/ATCC HS 578T 1.209 2.325 2.218 2.252 2.265 2.0421.393 90 93 95 75 16 2.65E−5 >1.00E−4  >1.00E−4 BT-549 0.984 2.104 2.0592.030 2.089 1.801 0.840 96 93 99 73 −15 1.83E−5 6.80E−5 >1.00E−4 T-47D0.661 1.698 1.679 1.636 1.733 1.289 0.423 98 94 103 61 −36 1.29E−54.24E−5 >1.00E−4 MDA-MB- 0.972 2.032 1.966 1.875 1.887 1.187 0.735 94 8586 20 −24 3.55E−6 2.85E−5 >1.00E−4 468

TABLE 18 NCI five dose result for JVM-96 Log10 Concentration Time MeanOptical Densities Percent Growth Panel/Cell Zero Ctrl −8.0 −7.0 −6.0−5.0 −4.0 −8.0 −7.0 −6.0 −5.0 −4.0 GI50 TGI LC50 Leukemia CCRF-CEM 0.5391.740 1.732 1.746 1.519 0.482 0.275 99 100 82 −11 −49 2.20E−67.66E−6 >1.00E−4  HL-60(TB) 0.667 2.556 2.384 2.139 2.111 0.636 0.348 9178 76 −5 −48 2.12E−6 8.75E−6 >1.00E−4  MOLT-4 0.612 2.163 2.117 2.2342.324 1.144 0.462 97 105 110 34 −25 6.22E−6 3.82E−5 >1.00E−4  RPMI-82260.957 2.219 2.290 2.302 2.148 1.243 0.495 106 107 94 23 −48 4.16E−62.09E−5 >1.00E−4  SR 0.252 1.042 0.919 0.963 0.859 0.347 0.164 84 90 7712 −35 2.59E−6 1.80E−5 >1.00E−4  Non-Small Cell Lung Cancer A549/ATCC0.398 1.375 1.295 1.309 1.417 1.214 0.134 92 93 104 83 −66 1.67E−53.61E−5 7.78E−5 HOP-62 0.830 1.790 1.738 1.724 1.766 1.741 0.389 95 9398 95 −53 2.01E−5 4.37E−5 9.52E−5 HOP-92 0.944 1.514 1.473 1.477 1.4580.924 0.068 93 93 90 −2 −93 2.72E−6 9.47E−6 3.37E−5 NCI-H226 0.851 2.1462.091 2.107 2.074 1.665 0.329 96 97 94 63 −61 1.27E−5 3.20E−5 5.10E−5NCI-H23 0.672 1.930 1.881 1.965 1.973 1.722 0.383 96 103 103 83 −431.84E−5 4.57E−5 >1.00E−4  NCI-H322M 0.888 2.093 2.001 2.031 2.075 1.9720.950 92 95 99 90 5 2.96E−5 >1.00E−4  >1.00E4   NCI-H460 0.386 3.1743.223 3.235 3.204 2.918 0.258 102 102 101 91 −33 2.13E−5 5.39E−5>1.00E4   NCI-H522 1.103 1.880 1.890 1.893 1.722 0.381 0.247 101 102 80−66 −78 1.60E−6 3.54E−6 7.82E−6 Colon Cancer COLO 205 0.527 1.425 1.5061.466 1.449 0.539 0.054 109 105 103 1 −90 3.30E−6 1.03E−5 3.66E−5HCC-2998 0.568 1.857 1.843 1.872 1.961 1.552 0.055 99 101 108 76 −901.44E−5 2.87E−5 5.73E−5 HCT-116 0.207 1.551 1.516 1.456 1.504 0.386−0.002 97 93 97 13 −100 3.62E−6 1.31E−5 3.62E−5 HCT-15 0.284 2.158 2.0322.035 1.960 0.580 0.035 93 93 8.9 16 −88 3.43E−6 1.42E−5 4.31E−5 KM120.508 2.629 2.581 2.630 2.718 2.468 0.108 98 100 104 92 −79 1.77E−53.46E−5 6.79E−5 SW-620 0.314 2.531 2.517 2.499 2.502 0.810 0.105 99 9999 22 −67 4.35E−6 1.78E−5 6.49E−5 CNS Cancer SF-268 0.564 1.919 1.8781.896 1.883 1.275 0.966 97 98 97 52 −71 1.05E−5 2.67E−5 6.76E−5 SF-2950.641 2.532 2.408 2.361 2.461 2.175 0.253 93 91 96 81 −61 1.66E−53.74E−5 8.42E−5 SF-539 0.954 2.492 2.432 2.264 2.398 1.079 0.124 96 8594 8 −87 3.25E−6 1.22E−5 4.08E−5 SNB-19 0.705 2.241 2.136 2.176 2.0591.818 0.401 93 96 88 72 −43 1.56E−5 4.23E−5 >1.00E−4  SNB-75 0.763 1.5191.369 1.282 1.275 1.073 0.043 80 69 68 41 −94 4.59E−6 2.01E−5 4.70E−5U251 0.597 1.881 1.779 1.790 1.872 1.726 0.105 92 93 99 88 −82 1.67E−53.28E−5 6.45E−5 Melanoma LOX IMVI 0.316 2.075 2.047 2.036 2.125 0.7500.043 98 98 103 25 −86 4.74E−6 1.67E−5 4.70E−5 M14 0.452 1.526 1.5011.433 1.464 0.833 0.062 98 91 96 35 −86 5.75E−6 1.95E−5 5.03E−5 MDA-MB-0.554 2.517 2.451 2.308 2.327 1.188 0.957 97 89 90 32 −72 4.95E−62.04E−5 6.19E−5 435 SK-MEL-2 1.069 1.923 1.836 1.852 1.894 1.557 0.26190 92 97 57 −76 1.13E−5 2.69E−5 6.41E−5 SK-MEL-28 0.627 1.739 1.6551.642 1.603 0.820 0.099 92 91 8.8. 17 −84 3.44E−6 1.48E−5 4.60E−58K-MEL-5 0.621 2.416 2.367 2.373 2.227 1.576 0.068 97 98 8.9 53 −891.05E−5 2.37E−5 5.31E−5 UACC-257 1.042 1.937 1.825 1.849 1.892 1.4660.139 88 90 95 47 −87 8.82E−6 2.26E−5 5.32E−5 UACC-62 0.774 2.836 2.7922.804 2.627 1.625 0.098 98 98 90 41 −87 6.61E−6 2.09E−5 5.12E−5 OvarianCancer IGROVI 0.763 2.251 2.350 2.338 2.358 1.943 0.362 107 106 107 79−53 1.67E−5 3.99E−5 9.55E−5 OVCAR-3 0.513 1.638 1.587 1.712 1.639 0.7820.010 96 107 100 24 −98 4.54E−6 1.57E−5 4.03E−5 OVCAR-4 0.665 1.4131.385 1.341 1.317 1.044 0.100 96 90 87 51 −85 1.01E−5 2.36E−5 5.52E−5OVCAR-5 0.693 1.481 1.428 1.354 1.392 1.181 0.130 93 84 89 62 −811.21E−5 2.71E−5 6.05E−5 OVCAR-8 0.632 2.020 1.954 1.947 2.086 1.5050.197 95 95 105 63 −69 1.25E−5 3.00E−5 7.20E−5 NCI/ADR- 0.494 1.7151.721 1.726 1.795 1.630 0.563 101 101 107 93 63.11E−5 >1.00E−4  >1.00E−4  RES SK-OV-3 0.933 1.575 1.571 1.602 1.6111.611 0.757 99 104 106 106 −19 2.80E−5 7.05E−5 >1.00E−4  Renal Cancer786-0 0.506 1.660 1.777 1.750 1.781 0.856 0.045 94 92 94 26 −91 4.43E−61.66E−5 4.44E−5 A498 1.386 2.309 2.268 2.373 2.265 2.073 0.068 96 107 9574 −95 1.39E−5 2.75E−5 5.42E−5 ACHN 0.448 1.776 1.745 1.697 1.671 0.8090.087 98 94 92 27 −81 4.45E−6 1.79E−5 5.19E−5 CAKI-1 0.613 2.568 2.4232.280 2.317 1.414 0.045 93 85 87 41 −93 6.37E−6 2.03E−5 4.79E−5 RXF 3930.735 1.273 1.235 1.272 1.236 0.817 0.147 93 100 93 15 −80 3.57E−61.44E−5 4.84E−5 SN12C 0.945 3.077 3.003 3.075 2.961 2.211 0.581 97 10095 59 −39 1.25E−5 4.04E−5 >1.00E−4  TK-10 0.971 1.914 1.937 1.942 1.9081.110 0.009 102 103 99 15 −99 3.83E−6 1.35E−5 3.792-5 UO-31 0.831 2.1922.015 2.027 2.083 1.526 0.105 87 88 92 51 −87 1.02E−5 2.34E−5 5.37E−5Prostate Cancer PC-3 0.671 1.469 1.391 1.408 1.414 1.293 0.218 90 92 9378 −68 1.56E−5 3.43E−5 7.57E−5 DU-145 0.354 1.507 1.490 1.575 1.4880.535 0.012 99 106 98 16 −97 3.84E−6 1.39E−5 3.84E−5 Breast Cancer MCF70.349 1.821 1.676 1.660 1.679 0.502 0.112 90 89 90 10 −68 3.20E−61.36E−5 5.89E−5 MDA-MB- 0.612 1.382 1.359 1.355 1.313 0.914 0.160 97 9691 39 −74 6.19E−6 2.22E−5 6.15E−5 231/ATCC HS 578T 1.009 2.160 2.1022.176 2.088 1.713 0.958 95 101 94 61 −5 1.47E−5 6.37E−5 >1.00E−4  BT-5490.820 1.560 1.576 1.576 1.511 1.060 0.022 102 139 93 32 −97 5.14E−61.78E−5 4.31E−5 T-47D 0.857 1.577 1.578 1.574 1.536 0.953 0.245 100 10094 13 −71 3.52E−6 1.44E−5 5.59E−5 MDA-MB- 0.681 1.184 1.123 1.153 1.0010.615 0.192 88 94 64 −10 −72 1.54E−6 7.38E−6 4.46E−5 468

What is claimed is:
 1. A compound comprising Formula (I) or (II):

wherein: X is O or S; R¹ and R² are independently selected from thegroup consisting of —OR³, —O-alkyl-NR³R⁴, —SR³, —S-alkyl-NR³R⁴,alkyl-C(O)NR³R⁴, and -alkyl-R⁵ or when X is S, R¹ is —NR³R⁴; R³ isselected from the group consisting of hydrocarbyl, substitutedhydrocarbyl, and R⁵; R⁴ is selected from the group consisting ofhydrogen, hydrocarbyl, and substituted hydrocarbyl; R⁵ is an optionallysubstituted nitrogen-containing heterocyclic ring; one or more of R³ andR⁴ may form part of a ring or ring system chosen from the groupconsisting of heterocyclic, substituted heterocyclic, and combinationsthereof; and when R⁴ is hydrogen, R³ is selected from the groupconsisting of alkyl, R⁵, and substituted hydrocarbyl having at least onehydroxyl or R⁵.
 2. The compound of claim 1, wherein R¹ and R² areselected from the group consisting of alkoxy, alkylamino, dialkylamino,dialkylaminoalkoxy, heterocyclylalkoxy, hydroxyalkylamino,heterocycylamino, and heterocycylalkylamino.
 3. The compound of claim 2,wherein R¹ and R² are selected from the group consisting of methylamino,dimethylamino, hydroxyhexylamino, hydroxyethylamino, pyrrolyl,pyrrolidinyl, pyridinyl, piperdinyl, pyrazinyl, piperazinyl,pyrimidinyl, imidazolyl, triazolyl, hydroxypiperdinyl,difluoropiperdinyl, triazolylamino, methylthiotriazolylamino,morpholinyl, morpholinylethylamino, pyridinylmethylamino,piperdinylethylamino, pyridinylethylamino, morpholinylpropylamino,imidiazolylpropylamino, methoxy, dimethylaminoethoxy, piperdinylpropoxy,piperdinylethoxy, pyrrolidinylethoxy, morpholinylethyoxy,piperidinylethoxyhydroxyethylthio, and piperdinylethyl.
 4. The compoundof claim 2, wherein R¹ and R² are independently selected from the groupconsisting of imidazolylpropylaminocarbonylethylcarbonyl,difluoropiperinylcarbonylethylcarbonyl,methylthiotriazolylaminocarbonylethylcarbonyl,chloropyridinylmethylaminocarbonylethylcarbonyl,methylpiperdinylcarbonylethylcarbonyl, and methylpiperazinylcarbonylethylcarbonyl.
 5. The compound of claim 1, wherein R¹is R⁵, and R² is dialkylamino.
 6. The compound of claim 1, wherein oneor more R¹, R², R³, R⁴, or R⁵ is substituted with at least one selectedfrom the group consisting of methyl, ethyl, propyl, cyano,C₁-C₃-alkylamino, carboxyl, hydroxyl, trifluoromethyl, thio, alkylthio,and halogen.
 7. A pharmaceutically acceptable salt comprising a compoundof claim 1.